# ent

id: cord-255536-x1z2o9gs
type: DISEASE
entity:
  Herpes simplex virus type 1 genome Human telomere oncogenic promoter and 5 0 UTR G quadruplexes diverse


id: cord-262184-uxyb4vih
type: DISEASE
entity:
  human immunodeficiency virus reverse transcriptase and human DNA polymerases Triphosphates of the two


id: cord-008716-38sqkh9m
type: PROTEIN
entity:
  surface glycoproteins G and F of RSV HN and F of PIV and HA and NA of influenza or to capsid proteins hexon


id: cord-266520-n439dwcx
type: DISEASE
entity:
  herpes simplex virus type 1 HSV 1 mRNAs encoding essential viral proteins including glycoprotein B UL27 the infected cell protein 8 ICP8 UL29 and ICP27


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  Ulm Albert Einstein Allee 11 89081 Ulm Germany 2 IPF PharmaCeuticals GmbH Feodor Lynen Strasse 31 30625 Hannover Germany A


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  British Columbia Vancouver BC Canada V6T 1Z3 2 GE Healthcare Bio Sciences Piscataway NJ 08855 USA 3 British Columbia Center for Disease Control Vancouver BC Canada V5Z 4R4


id: cord-020010-q58x6xb0
type: CELL_LINE
entity:
  British Columbia Vancouver BC Canada 2 AVI BioPharma Inc Corvallis OR USA Background Coxsackievirus B3 CVB3


id: cord-020010-q58x6xb0
type: DNA
entity:
  REP 9 Adriana Garozzo 1 Rossella Timpanaro 1 Aldo Stivala 1 Gianna Tempera 1 Christian C C Cutrì 2 Angelo Castro 1 1 Department


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Biologic and Materials Sciences School of Dentistry 3 Interdepartmental Graduate Program


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Life and Environmental Sciences Faculty of Engineering Chiba Institute of Technology Chiba


id: cord-020010-q58x6xb0
type: ORG
entity:
  University of Alabama School of Medicine Birmingham AL USA 2 Department of Medicine University of California San Diego


id: cord-020010-q58x6xb0
type: ORG
entity:
  Department of Pediatrics University of Alabama School of Medicine Birmingham AL USA 2 Southern Research Institute


id: cord-020010-q58x6xb0
type: ORG
entity:
  the Rocky Mountain Regional Centers of Excellence NIH Laboratory of Virology Department of Biological Chemistry School of Sciences


id: cord-020010-q58x6xb0
type: ORG
entity:
  the Virology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Slobodan Paessler 1 Laure Deflubé 1 Andrew Vaillant 2


id: cord-020010-q58x6xb0
type: LAW
entity:
  the REP 9 Adriana Garozzo 1 Rossella Timpanaro 1 Aldo Stivala 1 Gianna Tempera 1 Christian C C Cutrì 2 Angelo Castro 1 1 Department of Microbiological Sciences University of Catania Via Androne 8 95124


id: cord-020010-q58x6xb0
type: ORG
entity:
  Leuven Belgium 2 Department of Chemistry University of Nevada Reno USA 3 Service de Neurovirologie Fontenay aux


id: cord-020010-q58x6xb0
type: ORG
entity:
  Institute of Microbiology 2 Institute of Experimental Pathology and Parasitology 3 Institute of Botany


id: cord-020010-q58x6xb0
type: EVENT
entity:
  International Conference on Antiviral Research ISAR Conference Committee Future Conferences Acknowledgement


id: cord-020010-q58x6xb0
type: DISEASE
entity:
  influenza A H5N1 virus efficacy was compared to similar dosages of oseltamivir and oseltamivir carboxylate


id: cord-020010-q58x6xb0
type: CHEMICAL
entity:
  Magnani 4 E Garaci 5 A T Palamara 1 1 Department Public Health Sciences University Rome La Sapienza Rome Italy


id: cord-020010-q58x6xb0
type: CHEMICAL
entity:
  5 methylthio 3 4 3 phenyl 1 propoxy phenyl isoxazol 4 carbonitrile ON 7 and 5 methylthio 3 4 4 phenoxy 1 buthoxy phenyl isoxazol 4 carbonitrile


id: cord-277443-mv7sk5aa
type: PROTEIN
entity:
  interferon gamma inducible protein 10 IP 10 monocyte chemoattractant protein 1 MCP 1 interleukin 6 IL 6


id: cord-277443-mv7sk5aa
type: ORG
entity:
  the Virology Branch National Institute of Allergic and Infectious Diseases National Institutes of Health


id: cord-008761-b36x05fn
type: EVENT
entity:
  Mechanisms of Production and Action Mechanisms of Production and Action Proceedings of Symposium on Clinical Use


id: cord-271638-0wsyl7vk
type: GGP
entity:
  myricetin 1 25 2 5 5 10 μM for 1 h at 37 C before infection then after adsorption the media containing myricetin


id: cord-271638-0wsyl7vk
type: GGP
entity:
  myricetin 2 5 5 10 20 μM treatment did not significantly influence the total expression levels of EGFR PI3K


id: cord-270498-hh6h50t2
type: PROTEIN
entity:
  anti phospho p38 1 1000 Cell Signaling anti phospho JNK 1 1000 Cell Signaling anti ERK1 2 1 1000 Cell Signaling anti p38 1 1000 Cell Signaling


id: cord-286831-ni7qfjk9
type: CELL_LINE
entity:
  ATCC American Type Culture Collection Manassas VA USA PEDV CV 777 porcine epidemic diarrhea virus was obtained from national veterinary


id: cord-286831-ni7qfjk9
type: DNA
entity:
  PEDV 5 CGGTTCTATTCCCGTTGATG 3 and 5 CCACAACCGAATGCTATTGA 3 actin 5 GCCATGTACG TTGCTATCCAGGCTG 3 and 3 AGCCGTGGCCATCTCTTGCTCGAAG 5 PCR amplified products


id: cord-286831-ni7qfjk9
type: GGP
entity:
  interferon riboflavin tannic acid quercetin apigenin luteolin catechin quercetrin genistin hesperidin rutin


id: cord-286831-ni7qfjk9
type: CHEMICAL
entity:
  glycyrrhizin interferon riboflavin tannic acid quercetin apigenin luteolin catechin quercetrin genistin hesperidin rutin


id: cord-264308-y6xuxj16
type: PROTEIN
entity:
  protein 10 IL 10 interleukin 10 IL 1b interleukin 1 beta IFN c interferon gamma PPAR c peroxisome proliferator activated receptor gamma


id: cord-264308-y6xuxj16
type: PROTEIN
entity:
  CXCR3 chemokine C X C motif receptor 3 TNFR1 tumour necrosis factor alpha receptor 1 IL 1R interleukin 1 receptor MIP 1 macrophage inflammatory protein 1 CCR2 C C chemokine receptor type 2


id: cord-264308-y6xuxj16
type: GGP
entity:
  IL 10 interleukin 10 IL 1b interleukin 1 beta IFN c interferon gamma PPAR c peroxisome proliferator activated receptor gamma EGCG epigallocatechin


id: cord-264308-y6xuxj16
type: GGP
entity:
  CXCR3 chemokine C X C motif receptor 3 TNFR1 tumour necrosis factor alpha receptor 1 IL 1R interleukin 1 receptor MIP 1 macrophage inflammatory protein 1 CCR2 C C chemokine receptor type 2 GM CSF Granulocyte


id: cord-264308-y6xuxj16
type: CHEMICAL
entity:
  1 beta IFN c interferon gamma PPAR c peroxisome proliferator activated receptor gamma EGCG epigallocatechin gallate


id: cord-264308-y6xuxj16
type: DISEASE
entity:
  lung bronchus pulmonary artery and pulmonary vein respectively Scale bar 200 lm D H Live dead staining assay Lung


id: cord-297398-40bshqly
type: GGP
entity:
  p38 mitogen activated protein kinase pathways date 2019 11 18 journal Antiviral Res DOI 10 1016 j antiviral 2019 104651 sha 44ce728e9777a6644404a15f6945116b189f3c17 doc_id 297398 cord_uid 40bshqly Emerging coronaviruses CoVs


id: cord-283739-p7b4mtbl
type: DISEASE
entity:
  acute respiratory syndrome coronavirus SARS CoV Middle East respiratory syndrome coronavirus MERS CoV


id: cord-291143-nkv1h3uh
type: PROTEIN
entity:
  alpha E beta 7 integrin Respiratory syncytial virus virology reverse genetics and pathogenesis of disease Hyperattenuated recombinant influenza A virus nonstructural proteinencoding vectors


id: cord-291143-nkv1h3uh
type: ORG
entity:
  Airway Resident Memory CD8 T Cells Provide Antigen Specific Protection against Respiratory Virus Challenge


id: cord-291143-nkv1h3uh
type: WORK_OF_ART
entity:
  Production Boosting of Cross Reactive and Protection Associated T Cells in Children After Live Attenuated Influenza Vaccination Intranasal


id: cord-291143-nkv1h3uh
type: DISEASE
entity:
  epithelial damage peribronchovascular cell infiltrate and interstitial alveolar cell infiltrate Epithelial damage


id: cord-312688-12san3m7
type: GGP
entity:
  Ser protease inhibitor leupeptin unselective Cys protease inhibitors E 64 and E 64d and its recent derivatives


id: cord-260735-3c33r1os
type: PROTEIN
entity:
  rabbit polyclonal antibody dilution 1 500 Santa Cruz Biotechnology Santa Cruz CA peroxidase conjugated goat anti rabbit IgG dilution 1 20 000 MP Biomedicals Cappel Solon OH and chemiluminescence West Femto Thermo Fisher Scientific Pierce Rockford IL


id: cord-260735-3c33r1os
type: CHEMICAL
entity:
  mercaptoethanol ethacrynic acid lipoic acid cytosine arabinoside AraC methylthiazolyldiphenyl tetrazolium bromide MTT


id: cord-285856-0sw3wt1i
type: CELL_LINE
entity:
  Human embryonic lung HEL fibroblasts human cervix epithelial HeLa African green monkey kidney Vero and Crandell feline kidney CrFK cells


id: cord-285856-0sw3wt1i
type: GGP
entity:
  dopamine 6c N 4 aminophenyl piperidine 6d and 4phenyl benzylamine 6e Based on the observation that compound 8e


id: cord-281385-oxohdfpu
type: CHEMICAL
entity:
  ribose 2 0 O position of the RNA to complete the type 1 cap formation m7GpppN RNA m7GpppNm Both N 7 and 2 0 O methylations use S adenosyl L methionine SAM


id: cord-329494-cdn52epy
type: CHEMICAL
entity:
  oligonucleotides Z F 5 GGATCCATGGGCAACTGCAACGGGGCATC 3 and Z trunc R 5 AAAAGCGGCCGCCTGGTGGTGGTGCTGTTGGCT 3 containing a BamHI


id: cord-308110-cco3aq4n
type: ORG
entity:
  National Institutes of Biomedical Innovation Health and Nutrition and National Institute of Infectious Diseases


id: cord-253825-d9borky8
type: CHEMICAL
entity:
  ethyl 6 bromo 4 dimethylamino methyl 5 hydroxy 1 methyl 2 phenylthio methyl indole 3 carboxylate hydrochloride monohydrate


id: cord-253825-d9borky8
type: CHEMICAL
entity:
  ethyl 6 bromo 5 hydroxy 1H indole 3 carboxylates Identification of novel 5 hydroxy 1H indole 3 carboxylates


id: cord-278876-il7g78w1
type: ORG
entity:
  Hokkaido University s Research Center for Zoonosis Control the Global Institution for Collaborative Research and Education


id: cord-337645-t6py0oyw
type: DNA
entity:
  simian virus 40 SV40 rotavirus enterovirus and rhinovirus Suzuki and Suzuki 2006 The binding of enveloped viruses to specific cellular receptors


id: cord-332952-d5l60cgc
type: ORG
entity:
  the Coalition for Epidemic Preparedness Innovations CEPI the Korean Ministry of Food and Drug Safety


id: cord-299964-sn5o3ugb
type: WORK_OF_ART
entity:
  The Ubiquitin proteasome System Is Necessary for the Efficient Replication of Human Astrovirus Deubiquitinating


id: cord-312965-5hcb15xc
type: DISEASE
entity:
  human immunodeficiency virus severe acute respiratory syndrome SARS virus influenza virus and herpes simplex virus Rhule


id: cord-297531-et1sli23
type: PROTEIN
entity:
  secondary antibody fluorescein isothiocyanate FITC conjugated goat anti mouse IgG Abcam Hangzhou China The


id: cord-288146-xqxznv1r
type: PROTEIN
entity:
  pp1a 2187 pp1a 2207 pp1a 2340 pp1a 2546 pp1a 2755 pp1a 2990 pp1a 3444 pp1a 3687 pp1a 3709 Spike 978 Spike 1167 Spike 1203


id: cord-298938-xemarhlv
type: DNA
entity:
  424 bp fragment nucleotides 382 806 p69 71 sense 5 CAATCAGCGAGGCCAGTAATC3 and p69 71 antisense 5 CTTGACGATTTTGTGCCGCTC3


id: cord-316503-wtmmewiz
type: DISEASE
entity:
  arenaviruses Lymphocytic choriomeningitis virus LCMV Tacaribe virus Pichinde virus and Junin virus vaccine strain Candid 1 Neuman


id: cord-316503-wtmmewiz
type: DISEASE
entity:
  influenza A virus in cell cultures with morpholino oligomers Fomivirsen clinical pharmacology and potential drug interactions Postexposure


id: cord-316996-8yimrpaz
type: DISEASE
entity:
  decreases in red blood cells haematocrit and hemoglobin were identified together with an increased reticulocyte count


id: cord-295470-mua0qvst
type: GGP
entity:
  NTZ 0 2 5 μM and MZR 0 20 μM on FCV The ZIP model in SynergyFinder was used to analyze the combined effects of the drugs and plot the results The synergy score for the ZIP model


id: cord-336093-ic6q6ke8
type: PROTEIN
entity:
  CoV SARS coronavirus nsp nonstructural protein N7 MTase guanine N7 methyltransferase 2 0 O MTase 2 0 O methyltransferase AdoMet S adenosyl L methionine AdoHcy S adenosyl L homocysteine ATA aurintricarboxylic acid IC


id: cord-336093-ic6q6ke8
type: RNA
entity:
  SARS coronavirus RNA cap 2 0 O methyltransferase nsp10 nsp16 complex Coronavirus nonstructural protein 16


id: cord-310469-v4p01rze
type: CELL_LINE
entity:
  São Paulo no 006 2004 In vitro antiviral evaluation was done with a plaque assay Livonesi et al 2006 Vero E6 cells


id: cord-316624-bqaqhp3m
type: GGP
entity:
  herpes simplex type 1 HSV 1 varicella zoster virus VZV Epstein Barr virus EBV human cytomegalovirus hepatitis A B


id: cord-314833-6fue84x6
type: DISEASE
entity:
  coronavirus particles SARS coronavirus unusual lability of the nucleocapsid protein Localization of an RNA binding domain in the nucleocapsid protein of the coronavirus mouse hepatitis virus The molecular


# bib

id: cord-008716-38sqkh9m
title: Current research on respiratory viral infections: Third International Symposium
author: Schmidt, Alexander C
date: 2001-06-01
txt: ./txt/cord-008716-38sqkh9m.txt
cache: ./cache/cord-008716-38sqkh9m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133842/
doi: 10.1016/s0166-3542(01)00136-x
abstract: nan
summary:
  Renewed efforts in vaccine development against respiratory viruses began in the 1960s with the observation that infants and young children, after having recovered from respiratory tract infection with adenoviruses, shed virus from their gastrointestinal tract for an extended period of time without experiencing gastrointestinal symptoms. Earlier studies of viral pathogens in immunocompromised adults indicated that CMV, herpes simplex, influenza, parainfluenza, rhinovirus, adenovirus, enterovirus, and RSV cause lower respiratory infection (Connolly et al., 1994) . Children with RSV, adenovirus or influenza virus infections have a 30% risk of developing AOM within 2 weeks of the onset of the respiratory tract infection (Henderson et al., 1982) , and coinfection with bacteria and viruses also adversely influences the outcome of AOM. Populations at high risk for complications resulting from respiratory viral infections are now better defined and a more targeted prophylaxis is possible, be it passive prophylaxis against RSV disease with monoclonal antibody preparations or active prophylaxis with influenza-or adenovirus vaccines.


id: cord-008761-b36x05fn
title: The interferon system as a basis for antiviral therapy or prophylaxis
author: Billiau, A.
date: 2012-02-26
txt: ./txt/cord-008761-b36x05fn.txt
cache: ./cache/cord-008761-b36x05fn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134133/
doi: 10.1016/s0166-3542(85)80020-6
abstract: nan
summary:
  Possessing satisfactory answers to these questions is essential, not only to understand the natural role of the interferon system in virus disease but also to assess possible applications in medicine, in particular the use of interferons or interferoninducing substances as antiviral drugs. Interferon prepared from mouse cell lines infected with Newcastle disease virus is a mixture of a and B (6) . The main difference between these products and their natural-source-derived counterparts is that they contain only a single subtype, namely a2'' While it is known that different subtypes of HuIFN-~ may differ in their antiviral potency depending on the cells on which they are tested, it is not yet known whether this has any repercussion for the clinical effects. Although these side-chains do not playa significant role in the effects of the IFN-S on cells, the pharmacokinetic behavior of this rDd-IFN-S was found to be rather different from that of natural fibroblast-derived interferon (8) .


id: cord-010247-cug21fnf
title: An ELISA system for evaluating antiretroviral activity against Rauscher murine leukemia virus
author: Hollingshead, Melinda G.
date: 1992-06-15
txt: ./txt/cord-010247-cug21fnf.txt
cache: ./cache/cord-010247-cug21fnf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173104/
doi: 10.1016/0166-3542(92)90060-i
summary:
  A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. In the case of this compound, the activity detected by the UV-XC plaque reduction assay was believed to result from cytotoxicity to the XC cells used as an overlay. The primary difference between the-ELISA assay and the UV-XC plaque reduction assay is in the drug concentrations required to suppress the virus production endpoint. The UV-XC plaque reduction assay measures the capacity of an antiviral compound to reduce production of infectious virus.

abstract:
  A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The activity of various antiviral compounds demonstrated in this assay system has been compared to their activity in the UV-XC plaque reduction assay, which has been used historically for evaluating anti-R-MuLV compounds. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. The assay reagents are readily available and the assay system is amenable to automated data collection systems. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. This system is less sensitive than the classical UV-XC plaque reduction assay; however, it does offer an alternative to the time-consuming and labor-intensive plaque assay.


id: cord-020010-q58x6xb0
title: 19th ICAR Abstracts:
author: nan
date: 2006-03-13
txt: ./txt/cord-020010-q58x6xb0.txt
cache: ./cache/cord-020010-q58x6xb0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133865/
doi: 10.1016/j.antiviral.2006.02.001
abstract: nan
summary:
  In the present study we reported the antiviral activity of neuraminidase inhibitor oseltamivir against lethal H5N1 influenza virus infection in ferrets, an appropriate animal model that closely resembles clinical signs of human influenza. Earl Kern 1 , Kathy Keith 2 , Robert Jordan 2 , Dennis Hruby 2 , Debra Quenelle 2 1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL, USA; 2 SIGA Technologies, Inc., Corvallis, OR, USA Although cidofovir (CDV) has been approved as an investigational new drug for emergency treatment of smallpox, its lack of oral activity and dose limiting toxicity dictates a need for continued development of better therapeutic agents for this potential bioterror disease. The in vitro antiviral activity of one of the most selective compounds, i.e. CHI-033, was assessed by (i) MTS-based cytopathic effect assays, (ii) virus yield reduction assays, (iii) real-time quantitative PCR (RT-QPCR) and (iv) by monitoring viral antigen expression.


id: cord-023608-w2g7v7g1
title: ISAR News
author: nan
date: 2017-10-20
txt: ./txt/cord-023608-w2g7v7g1.txt
cache: ./cache/cord-023608-w2g7v7g1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172721/
doi: 10.1016/s0166-3542(17)30664-2
abstract: nan
summary:
  ICAR retains its flavor and personality, providing an interdisciplinary forum at which investigators involved in basic, translational, and clinical research worldwide meet to review recent developments in all areas of antiviral research, drug and vaccine development. Additionally, satellite activities such as the Women in Science Roundtable, the Career Development Panel and the New Member and First Time Attendee luncheon (The Happy Hour) provided an opportunity to discuss other issues of relevance. With so many different competing conferences and meetings to attend and a long economic crisis of which scientific research did not escape, ISAR has gone through great financial efforts to continue supporting the participation of students, postdocs and young investigators. The TCFF Awards support the professional development of women with potential to make significant contributions to the field of Antiviral Research by providing funds to attend a conference, visit another laboratory, take a course, or acquire specialized training.


id: cord-253825-d9borky8
title: Arbidol as a broad-spectrum antiviral: An update
author: Blaising, Julie
date: 2014-04-24
txt: ./txt/cord-253825-d9borky8.txt
cache: ./cache/cord-253825-d9borky8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24769245/
doi: 10.1016/j.antiviral.2014.04.006
summary:
  ARB has been shown to display antiviral in vitro and/or in vivo activity against a number of enveloped or non-enveloped RNA or DNA viruses, including influenza viruses A, B and C , respiratory syncytial virus, SARS-CoV, adenovirus, parainfluenza type 5, poliovirus 1, rhinovirus 14, coxsackievirus B5, hantaan virus, Chikungunya virus, HBV and HCV [reviewed in Boriskin et al. Shi and coworkers showed a greater inhibitory effect on influenza A H1N1 when ARB was added before infection or when it was pre-incubated with the virus (Shi et al., 2007) , suggesting that membrane impregnation and/or metabolites could underlie ARB antiviral activity (see Section 6.). Recently, Tannock and coworkers reported a potent antiviral activity of ARB on several virus families responsible of respiratory infections in animals and humans, in particular on influenza A H3N2 (IC50 12 lM), and the non-enveloped Picornaviridae poliovirus 1 and rhinovirus 14 (Brooks et al., 2012 ; see also Brooks et al., 2004) .

abstract:
  Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico-chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action. Recent studies suggest that ARB’s dual interactions with membranes and aromatic amino acids in proteins may be central to its broad-spectrum antiviral activity. This could impact on the virus itself, and/or on cellular functions or critical steps in virus-cell interactions, thereby positioning ARB as both a direct-acting antiviral (DAA) and a host-targeting agent (HTA). In the context of recent studies in animals and humans, we will discuss the prospective clinical use of ARB in various viral infections.


id: cord-254201-hqijd268
title: Radiolabeled antiviral drugs and antibodies as virus-specific imaging probes
author: Bray, Mike
date: 2010-08-13
txt: ./txt/cord-254201-hqijd268.txt
cache: ./cache/cord-254201-hqijd268.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354210006923
doi: 10.1016/j.antiviral.2010.08.005
summary:
  Such drugs and antibodies can therefore be thought of as probes for the detection of viral infections, suggesting that they might be used as radiolabeled tracers to visualize sites of viral replication by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. The only instance in which a pathogen-specific tracer has been employed to detect and track a virus has been the use of a radiolabeled thymidine analogue to image herpes simplex virus (HSV) infections, based on phosphorylation of the probe by the viral thymidine kinase (TK), which traps it within infected cells (Fig. 2) (Brader et al., 2009; Kuruppu et al., 2007) . However, although compounds that inhibit methylation by blocking the host cell enzyme, S-adenosylhomocyteine hydrolase, have potent broad-spectrum antiviral activity, they would not be suitable as virus-specific probes, because they do not bind to a viral target.

abstract:
  A number of small-molecule drugs inhibit viral replication by binding directly to virion structural proteins or to the active site of a viral enzyme, or are chemically modified by a viral enzyme before inhibiting a downstream process. Similarly, antibodies used to prevent or treat viral infections attach to epitopes on virions or on viral proteins expressed on the surface of infected cells. Such drugs and antibodies can therefore be thought of as probes for the detection of viral infections, suggesting that they might be used as radiolabeled tracers to visualize sites of viral replication by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. A current example of this approach is the PET imaging of herpes simplex virus infections, in which the viral thymidine kinase phosphorylates radiolabeled thymidine analogues, trapping them within infected cells. One of many possible future applications might be the use of a radiolabeled hepatitis C protease inhibitor to image infection in animals or humans and provide a quantitative measure of viral burden. This article reviews the basic features of radionuclide imaging and the characteristics of ideal tracer molecules, and discusses how antiviral drugs and antibodies could be evaluated for their suitability as virus-specific imaging probes. The use of labeled drugs as low-dose tracers would provide an alternative application for compounds that have failed to advance to clinical use because of insufficient in vivo potency, an unsuitable pharmacokinetic profile or hepato- or nephrotoxicity.


id: cord-255536-x1z2o9gs
author: Artusi, Sara
date: 2015-04-03
txt: ./txt/cord-255536-x1z2o9gs.txt
cache: ./cache/cord-255536-x1z2o9gs.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354215000807
doi: 10.1016/j.antiviral.2015.03.016
summary:
  The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G-quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. In the Epstein-Barr herpes virus (EBV), G-quadruplexes modulate EBV nuclear antigen 1 (EBNA1) activity and translation (Murat et al., 2014) ; in particular, BRACO-19 inhibited EBNA1-dependent stimulation of viral DNA replication http://dx.doi.org/10.1016/j.antiviral.2015.03.016 0166-3542/Ó 2015 Elsevier B.V. All rights reserved. We demonstrate that treatment with the G-quadruplex ligand BRACO-19 greatly stabilizes these sequences resulting in decrease of infectious viral particles, reduction of late viral transcripts, inhibition of Taq polymerase processing at the HSV-1 genome, specifically affecting viral DNA replication at G-quadruplex regions.

title:
  The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

abstract:
  Guanine-rich nucleic acids can fold into G-quadruplexes, secondary structures implicated in important regulatory functions at the genomic level in humans, prokaryotes and viruses. The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G-quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. Using biophysical, molecular biology and antiviral assays, we showed that the HSV-1 genome displays multiple clusters of repeated sequences that form very stable G-quadruplexes. These sequences are mainly located in the inverted repeats of the HSV-1 genome. Treatment of HSV-1 infected cells with the G-quadruplex ligand BRACO-19 induced inhibition of virus production. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. The last step targeted by BRACO-19 was viral DNA replication, while no effect on virus entry in the cells was observed. This work, presents the first evidence of extended G-quadruplex sites in key regions of the HSV-1 genome, indicates the possibility to block viral DNA replication by G-quadruplex-ligand and therefore provides a proof of concept for the use of G-quadruplex ligands as new anti-herpetic therapeutic options.


id: cord-255902-fxlbx84w
author: Shephard, Adrian
date: 2015-09-25
txt: ./txt/cord-255902-fxlbx84w.txt
cache: ./cache/cord-255902-fxlbx84w.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354215002235
doi: 10.1016/j.antiviral.2015.09.012
summary:
  In this study, we investigated whether these lozenges also have virucidal effects in vitro against two viruses associated with respiratory tract infections, parainfluenza virus type 3 and cytomegalovirus. These findings suggest that AMC/DCBA lozenge and hexylresorcinol lozenge have the potential to have local antiviral effects in patients with sore throat due to viral respiratory tract infections. AMC/DCBA lozenges have also been shown to have some virucidal effects in vitro on three enveloped viruses -RSV, influenza A virus and severe acute respiratory syndrome coronavirus (SARS-CoV) (Oxford et al., 2005) . This study investigated the in vitro virucidal activity of AMC/ DCBA alone and in a lozenge on two other enveloped viruses that can cause sore throat and respiratory illness -PIV type 3 (PIV3) and CMV (Bisno, 2001) . Taken together, these data support the use of these lozenges as a first-line treatment for sore throat caused by viral RTIs. Further investigation into the mechanisms of action and the clinical effects of AMC/DCBA and hexylresorcinol for the control of RTIs is warranted.

title:
  Virucidal action of sore throat lozenges against respiratory viruses parainfluenza type 3 and cytomegalovirus

abstract:
  Most respiratory tract infections are self-limiting and caused by viruses, and do not warrant antibiotic treatment. Despite this, patients with respiratory tract infections often receive antibiotics, fuelling the rise of antibiotic resistance. Therefore, there is a need to encourage patients to try alternative non-antibiotic therapies, which ideally treat the symptoms and the cause. Lozenges containing amylmetacresol and 2,4-dichlorobenzyl alcohol (AMC/DCBA lozenges) as well as lozenges containing hexylresorcinol have been shown to provide effective symptomatic relief for sore throat. In this study, we investigated whether these lozenges also have virucidal effects in vitro against two viruses associated with respiratory tract infections, parainfluenza virus type 3 and cytomegalovirus. Both viruses were incubated with AMC/DCBA lozenge, placebo lozenge or the active ingredients (AMC/DCBA) as free substances, and parainfluenza virus type 3 was incubated with hexylresorcinol lozenge, placebo lozenge or hexylresorcinol as a free substance. Virucidal effects were observed with the active lozenges and the active ingredients as free substances against both parainfluenza virus type 3 and cytomegalovirus. Mean reductions in viral titre were significantly greater compared with placebo lozenge and peak effects were observed for the shortest incubation time, 1 min. These findings suggest that AMC/DCBA lozenge and hexylresorcinol lozenge have the potential to have local antiviral effects in patients with sore throat due to viral respiratory tract infections. Use of such over-the-counter treatments for self-limiting respiratory tract infections may satisfy patients’ desire for an anti-infective medication and reduce the demand for antibiotics.


id: cord-256270-7e8zlt3t
title: Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro
author: Choy, Ka-Tim
date: 2020-04-03
txt: ./txt/cord-256270-7e8zlt3t.txt
cache: ./cache/cord-256270-7e8zlt3t.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S016635422030200X
doi: 10.1016/j.antiviral.2020.104786
summary:
  We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Among the 16 compounds we tested, remdesivir, lopinavir, homoharringtonine, and emetine dihydrochloride were found to inhibit SARS-CoV-2 replication in Vero E6 cells with EC 50 under 100 μM (Table 1) . Importantly, we observed that some of the compounds currently undergoing clinical trials such as ribavirin, favipiravir, oseltamivir, or baloxavir showed no apparent antiviral effect against the SARS-CoV-2 virus in vitro at concentrations under 100 μM (Table 1) .

abstract:
  An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.


id: cord-256280-ihj102hi
title: The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection
author: Takano, Tomomi
date: 2017-08-03
txt: ./txt/cord-256280-ihj102hi.txt
cache: ./cache/cord-256280-ihj102hi.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354217304424
doi: 10.1016/j.antiviral.2017.07.022
summary:
  title: The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection In this study, we investigated whether U18666A, the cholesterol synthesis and transport inhibitor, shows antiviral effects against type I FCoV. U18666A induced cholesterol accumulation in cells and inhibited type I FCoV replication. These findings suggest that cell membrane cholesterol plays an important role in type I FCoV infection. In order to confirm the effects of the accumulation of cholesterol on FCoV infection, fcwf-4 cells were pretreated with U18666A, followed by virus inoculation. When cells were pretreated with cholesterol biosynthesis inhibitors, only itraconazole significantly inhibited FCoV-I KU2 plaque formation. In addition, treatment of cells with U18666A did not influence the cellular cholesterol level, suggesting that U18666A inhibits type I FCoV replication at a concentration suppressing cholesterol transporter but not influencing the synthesis system. It was suggested that U18666A inhibits type I FCoV replication by suppressing the intracellular cholesterol transporter.

abstract:
  Feline infectious peritonitis (FIP) is a feline coronavirus (FCoV)-induced fatal disease in wild and domestic cats. FCoV exists in two serotypes. Type I FCoV is the dominant serotype worldwide. Therefore, it is necessary to develop antiviral drugs against type I FCoV infection. We previously reported that type I FCoV is closely associated with cholesterol throughout the viral life cycle. In this study, we investigated whether U18666A, the cholesterol synthesis and transport inhibitor, shows antiviral effects against type I FCoV. U18666A induced cholesterol accumulation in cells and inhibited type I FCoV replication. Surprisingly, the antiviral activity of U18666A was suppressed by the histone deacetylase inhibitor (HDACi), Vorinostat. HDACi has been reported to revert U18666A-induced dysfunction of Niemann-Pick C1 (NPC1). In conclusion, these findings demonstrate that NPC1 plays an important role in type I FCoV infection. U18666A or other cholesterol transport inhibitor may be considered as the antiviral drug for the treatment of cats with FIP.


id: cord-257271-jzmwy4yi
author: Lin, Jung-Chung
date: 2008-03-31
txt: ./txt/cord-257271-jzmwy4yi.txt
cache: ./cache/cord-257271-jzmwy4yi.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354208002064
doi: 10.1016/j.antiviral.2008.01.160
summary:
  Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). In previous years, we have shown that many nucleoside analogs selectively inhibit replication of Epstein-Barr virus (EBV) in vitro (Lin et al., 1983 (Lin et al., , 1984 (Lin et al., , 1985 (Lin et al., , 1987 (Lin et al., , 1991 (Lin et al., , 1992 Lin and Machida, 1988; Mar et al., 1995; for a review see Gershburg and Pagano, 2005; Lin, 2006) . As an assay system for drug effects we used Raji cells superinfected with P3HR-1 (LS) virus, which results in reactivation of the latent EBV infection and replication of virus. To determine the dose-dependent effect of GL derivatives, Raji cells were superinfected with P3HR-1 (LS) virus in the presence of various concentrations of compounds.

title:
  Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: Structure–activity relationships

abstract:
  Glycyrrhizic acid (18β-GL or GL) is a herbal drug with a broad spectrum of antiviral activities and pharmacological effects and multiple sites of action. Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). Here we tested the effects of 15 GL derivatives against EBV infection by scoring the numbers of cell expressing viral antigens and quantifying EBV DNA copy numbers in superinfected Raji cells. The derivatives were made either by transformation of GL on carboxyl and hydroxyl groups or by conjugation of amino acid residues into the carbohydrate part. We identified seven compounds active against EBV and all showed dose-dependent inhibition as determined by both assays. Among these active compounds, the introduction of amino acid residues into the GL carbohydrate part enhanced the antiviral activity in three of the seven active compounds. However, when Glu(OH)-OMe was substituted by Glu(OMe)-OMe, its antiviral activity was completely abolished. Introduction of potassium or ammonium salt to GL reduced the antiviral activity with no significant effect on cytotoxicity. The α-isomer (18α-GL) of 18β-GL was as potent as the β-form, but its sodium salt lost antiviral activity. The metabolic product of GL, 18β-glycyrrhetinic acid (18β-GA or GA), was 7.5-fold more active against EBV than its parental compound GL but, concomitantly, exhibited increased cytotoxicity resulting in a decreased therapeutic index.


id: cord-259480-1tqfoecc
author: Li, Huixin
date: 2016-03-02
txt: ./txt/cord-259480-1tqfoecc.txt
cache: ./cache/cord-259480-1tqfoecc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2016.03.003
doi: 10.1016/j.antiviral.2016.03.003
summary:
  To design an alternative vaccine for control of infectious bronchitis in chickens, three recombinant duck enteritis viruses (rDEVs) expressing the N, S, or S1 protein of infectious bronchitis virus (IBV) were constructed using conventional homologous recombination methods, and were designated as rDEV-N, rDEV-S, and rDEV-S1, respectively. After challenge with a homologous virulent IBV strain at 21 days post-immunization, vaccinated groups showed significant differences in the percentage of birds with clinical signs, as compared to the control group (p < 0.01), as the two covalent-vaccination groups and the rDEV-S group provided better protection than the rDEV-Nor rDEV-S1-vaccinated group. The N phosphoprotein is conserved among different IBV serotypes and can induce high titers of cross-reactive antibodies and cell-mediated immunity that protects chickens from acute infection, thus it is used as a target protein in designing vaccines against IB (Williams et al., 1992; Collisson et al., 2000; Seo et al., 1997) . Antibody responses of chickens vaccinated with recombinant duck enteritis viruses expressing the N, S or S1 gene of infectious bronchitis virus (IBV).

title:
  Recombinant duck enteritis viruses expressing major structural proteins of the infectious bronchitis virus provide protection against infectious bronchitis in chickens

abstract:
  To design an alternative vaccine for control of infectious bronchitis in chickens, three recombinant duck enteritis viruses (rDEVs) expressing the N, S, or S1 protein of infectious bronchitis virus (IBV) were constructed using conventional homologous recombination methods, and were designated as rDEV-N, rDEV-S, and rDEV-S1, respectively. Chickens were divided into five vaccinated groups, which were each immunized with one of the rDEVs, covalent vaccination with rDEV-N & rDEV-S, or covalent vaccination with rDEV-N & rDEV-S1, and a control group. An antibody response against IBV was detectable and the ratio of CD4(+)/CD8(+) T-lymphocytes decreased at 7 days post-vaccination in each vaccinated group, suggesting that humoral and cellular responses were elicited in each group as early as 7 days post-immunization. After challenge with a homologous virulent IBV strain at 21 days post-immunization, vaccinated groups showed significant differences in the percentage of birds with clinical signs, as compared to the control group (p < 0.01), as the two covalent-vaccination groups and the rDEV-S group provided better protection than the rDEV-N- or rDEV-S1-vaccinated group. There was less viral shedding in the rDEV-N & rDEV-S- (2/10) and rDEV-N & rDEV-S1- (2/10) vaccinated groups than the other three vaccinated groups. Based on the clinical signs, viral shedding, and mortality rates, rDEV-N & rDEV-S1 covalent vaccination conferred better protection than use of any of the single rDEVs.


id: cord-260071-z29b30sd
title: Highly potent anti-HIV-1 activity isolated from fermented Polygonum tinctorium Aiton
author: Zhong, Yu
date: 2005-03-27
txt: ./txt/cord-260071-z29b30sd.txt
cache: ./cache/cord-260071-z29b30sd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15911029/
doi: 10.1016/j.antiviral.2005.02.003
summary:
  All of these compounds are assumed to exert their anti-HIV activity by shielding the positively charged sites in the V3 loop region of the viral gp120 envelope glycoprotein, and interrupting virus attachment to the negatively charged heparan sulfate proteoglycans on cell surface, and inhibiting the specific binding to the CD4 receptor of CD4 + cells. PHA (1 g/ml, Sigma-Aldrich)/IL-2 (100 U/ml, Shionogi, Osaka, Japan) activated PBMCs were infected for 2 h with 20 ng of HIV-1 p24 Gag (X4/NL4-3 or R5/JRCSF) in the presence or absence of the Sukumo extract (0.64-400 g/ml), washed three times with PBS and cultured for 7 days in RPMI-1640 medium/10% FBS plus 100 U/ml IL-2 with or without the Sukumo extract. Sukumo extract was also evaluated for the inhibition of wild-type herpes simplex virus-1 replication in infected Vero cells, using a standard viral plaque assay (Fig. 1B) .

abstract:
  A water-soluble extract of fermented Polygonum tinctorium Aiton (Polygonaceae) called Sukumo, exhibited a potent inhibitory activity against HIV type 1 in vitro. The extract potently suppressed acute HIV-1 (III(B)) infection in MT-4 cells with EC(50) values of 0.5 μg/ml but exhibited low cytotoxicity to MT-4 cells even at a high concentration (CC(50) > 1000 μg/ml). It also inhibited giant cell formation in co-cultures of HIV-infected cells and uninfected Molt-4 cells. Sukumo extract was found to interact with both the viral envelope glycoprotein and cellular receptors, thus blocking virus-cell binding and virus-induced syncytium formation. There was a good correlation between the extract's anti-HIV-1 activity and its inhibitory effects on HIV-1 binding. It also suppressed replication of herpes simplex virus type 1 in Vero cells with an EC(50) of 11.56 μg/ml. On the other hand, there was no appreciable activity against influenza A virus, poliovirus or SARS corona virus when tested at concentrations ranging from 3.2–400 μg/ml as shown by microscopic image analysis for cytopathic effect (CPE). Physico-chemical studies revealed that the anti-HIV activity in the extract was essentially maintained after boiling at 100 °C in 1N HCl or 1N NaOH, and after treatment with 100 mM NaIO(4). The inhibitory activity of the extract was also not reduced after pronase digestion. The active factor in the extract is likely to be a novel compound(s) having a polyanionic substructure and a molecular weight of 10,000–50,000.


id: cord-260735-3c33r1os
title: Ethacrynic and α-lipoic acids inhibit vaccinia virus late gene expression
author: Spisakova, Martina
date: 2008-12-04
txt: ./txt/cord-260735-3c33r1os.txt
cache: ./cache/cord-260735-3c33r1os.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354208004348
doi: 10.1016/j.antiviral.2008.11.001
summary:
  In this paper, we report an original finding that two redox-modulating agents, the ethacrynic and α-lipoic acids (EA, LA), inhibit growth of vaccinia virus (VACV) in vitro. Therefore, we have first compared the effect of different redox-modulating agents on the growth of VACV, characterized by activity of luciferase expressed by a rVACV. HeLa G cells were infected with a rVACV expressing luciferase under control of a VACV late promoter p4b (Luc L; The results indicated that all tested concentrations of ␤mercapthoethanol, dithiothreitol and l-ascorbic acid significantly increased luciferase activity expressed by rVACV (500 M concentration of these agents increased luciferase activity to 150, 140, and 120% of the mock-treated controls; p < 0.05). In contrast to EA and LA, none of these agents inhibited VACV growth in HeLa G cells characterized by activity of the reporter luciferase expressed by a rVACV.

abstract:
  Smallpox was declared eradicated in 1980. However recently, the need of agents effective against poxvirus infection has emerged again. In this paper, we report an original finding that two redox-modulating agents, the ethacrynic and α-lipoic acids (EA, LA), inhibit growth of vaccinia virus (VACV) in vitro. The effect of EA and LA was compared with those of β-mercaptoethanol, DTT and ascorbic acid, but these agents increased VACV growth in HeLa G cells. The inhibitory effects of EA and LA on the growth of VACV were further confirmed in several cell lines of different embryonic origin, in epithelial cells, fibroblasts, macrophages and T-lymphocytes. Finally, we have analyzed the mechanism of action of the two agents. They both decreased expression of VACV late genes, as demonstrated by western blot analysis and activity of luciferase expressed under control of different VACV promoters. In contrast, they did not inhibit virus entry into the cell, expression of VACV early genes or VACV DNA synthesis. The results suggest new directions in development of drugs effective against poxvirus infection.


id: cord-262110-569a86u3
author: Tan, Chee Wah
date: 2014-04-24
txt: ./txt/cord-262110-569a86u3.txt
cache: ./cache/cord-262110-569a86u3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2014.04.004
doi: 10.1016/j.antiviral.2014.04.004
summary:
  Octaguanidinium-conjugated morpholino oligomers (vivo-MOs) are single-stranded DNA-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary RNA sequences. In this study, three octaguanidinium dendrimer conjugatedmorpholino oligomers (vivo-MOs) targeting the EV-71 internal ribosome entry site (IRES) core sequence and the RNA-dependent RNA polymerase (RdRP) were tested for their inhibitory effects against EV-71. After incubation, the inoculum was removed and replenished with maintenance medium (DMEM with 2% FBS) with or without vivo-MOs. The inhibitory effects of the vivo-MOs were evaluated by plaque assay, TaqMan real-time RT-PCR and western blot analysis 24 h post-infection (hpi) as previously described (Tan et al., 2012 . As shown in Fig. 2 , both vivo-MOs targeting the EV-71 IRES stemloop region exhibited significant antiviral activity against EV-71 infection with reduction of virus-induced CPE ( Fig. 2A) , plaque formation (Fig. 2B) , RNA (Fig. 2C ) and capsid expression (Fig. 2D ) in a dose-dependent manner.

title:
  Inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer-conjugated morpholino oligomers

abstract:
  Enterovirus 71 (EV-71) infections are generally manifested as mild hand, foot and mouth disease, but have been reported to cause severe neurological complications with high mortality rates. Treatment options remain limited due to the lack of antivirals. Octaguanidinium-conjugated morpholino oligomers (vivo-MOs) are single-stranded DNA-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary RNA sequences. In this study, inhibitory effects of three vivo-MOs that are complementary to the EV-71 internal ribosome entry site (IRES) and the RNA-dependent RNA polymerase (RdRP) were tested in RD cells. Vivo-MO-1 and vivo-MO-2 targeting the EV-71 IRES showed significant viral plaque reductions of 2.5 and 3.5 log(10)PFU/ml, respectively. Both vivo-MOs reduced viral RNA copies and viral capsid expression in RD cells in a dose-dependent manner. In contrast, vivo-MO-3 targeting the EV-71 RdRP exhibited less antiviral activity. Both vivo-MO-1 and 2 remained active when administered either 4 h before or within 6 h after EV-71 infection. Vivo-MO-2 exhibited antiviral activities against poliovirus (PV) and coxsackievirus A16 but vivo-MO-1 showed no antiviral activities against PV. Both the IRES-targeting vivo-MO-1 and vivo-MO-2 inhibit EV-71 RNA translation. Resistant mutants arose after serial passages in the presence of vivo-MO-1, but none were isolated against vivo-MO-2. A single T to C substitution at nucleotide position 533 was sufficient to confer resistance to vivo-MO-1. Our findings suggest that IRES-targeting vivo-MOs are good antiviral candidates for treating early EV-71 infection, and vivo-MO-2 is a more favorable candidate with broader antiviral spectrum against enteroviruses and are refractory to antiviral resistance.


id: cord-262184-uxyb4vih
author: Jockusch, Steffen
date: 2020-06-18
txt: ./txt/cord-262184-uxyb4vih.txt
cache: ./cache/cord-262184-uxyb4vih.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220302710?v=s5
doi: 10.1016/j.antiviral.2020.104857
summary:
  We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. Using the criteria above, our study examines 11 nucleotide analogues with sugar or base modifications (structures shown in Fig. 1 ) for their ability to inhibit the SARS-CoV-2 or SARS-CoV RdRps: Ganciclovir 5''-triphosphate, Carbovir 5''-triphosphate, Cidofovir diphosphate, Stavudine 5''-triphosphate, Entecavir 5''-triphosphate, 2''-O-methyluridine-5''-triphosphate (2''-OMe-UTP), 3''-O-methyluridine-5''triphosphate (3''-OMe-UTP), 2''-fluoro-2''-deoxyuridine-5''-triphosphate (2''-F-dUTP), desthiobiotin-16aminoallyl-uridine-5''-triphosphate (Desthiobiotin-16-UTP), biotin-16-aminoallyl-2''-deoxyuridine-5''triphosphate (Biotin-16-dUTP) and 2''-amino-2''-deoxyuridine-5''-triphosphate (2''-NH 2 -dUTP). We then performed polymerase extension assays with the library of nucleoside triphosphate analogues (Fig. 1) either alone or in combination with natural nucleotides: 2''-OMe-UTP, 3''-OMe-UTP, 2''-F-dUTP, 2''-NH 2 -dUTP, Biotin-UTP, desthiobiotin-16-UTP, Sta-TP, Cid-DP + UTP + ATP, Car-TP + UTP + ATP + CTP, Gan-TP + UTP + ATP + CTP, or Ent-TP + UTP + ATP + CTP, following the addition of a pre-annealed RNA template and primer to a pre-assembled mixture of the SARS-CoV and/or SARS-CoV-2 RdRp (nsp12) and the two cofactor proteins (nsp7 and nsp8).

title:
  A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses that Cause SARS and COVID-19

abstract:
  SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2’ or 3’ modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses’ exonuclease activity. We examined these nucleotide analogues for their ability to be incorporated by the RdRps in the polymerase reaction and to prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (triphosphates of Carbovir, Ganciclovir, Stavudine and Entecavir; 3’-OMe-UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2’-OMe-UTP), and 3 did not terminate the polymerase reaction (2’-F-dUTP, 2’-NH(2)-dUTP and Desthiobiotin-16-UTP). The coronaviruses possess an exonuclease that apparently requires a 2’-OH at the 3’-terminus of the growing RNA strand for proofreading. In this study, all nucleoside triphosphate analogues evaluated form Watson-Crick-like base pairs. The nucleotide analogues demonstrating termination either lack a 2’-OH, have a blocked 2’-OH, or show delayed termination. Thus, these nucleotide analogues are of interest for further investigation to evaluate whether they can evade the viral exonuclease activity. Prodrugs of five of these nucleotide analogues (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA-approved medications for treatment of other viral infections, and their safety profiles are well established. After demonstrating potency in inhibiting viral replication in cell culture, candidate molecules can be rapidly evaluated as potential therapies for COVID-19.


id: cord-263042-qdmunb9l
author: Zhao, Yongkun
date: 2016-11-24
txt: ./txt/cord-263042-qdmunb9l.txt
cache: ./cache/cord-263042-qdmunb9l.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354216303928
doi: 10.1016/j.antiviral.2016.11.016
summary:
  Passive transfer of equine immune antibodies significantly reduced virus titers and accelerated virus clearance from the lungs of MERS-CoV infected mice. Our data show that horses immunized with MERS-CoV VLPs can serve as a primary source of protective F(ab'')(2) for potential use in the prophylactic or therapeutic treatment of exposed or infected patients. Several research groups have developed and produced anti-MERS patientderived or humanized monoclonal neutralizing antibodies in vitro that were able to protect MERS-CoV infected mice (Corti et al., 2015; Li et al., 2015; Zhao et al., 2014) . Prophylactic or therapeutic treatment of MERS-CoV infected mice with either IgG or F(ab'') 2 significantly decreased the virus load in their lungs. In both prophylactic and therapeutic settings, passive transfer of equine immune antibodies resulted in a 2e4 log reduction of virus titers in the lungs of MERS-CoV infected mice, and accelerated virus clearance in the serum treated group (Fig. 5A, B) .

title:
  Passive immunotherapy for Middle East Respiratory Syndrome coronavirus infection with equine immunoglobulin or immunoglobulin fragments in a mouse model

abstract:
  Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a coronavirus (CoV), MERS-CoV. With the continuing spread of MERS-CoV, prophylactic and therapeutic treatments are urgently needed. In this study, we prepared purified equine F(ab’)(2) from horses immunized with MERS-CoV virus-like particles (VLPs) expressing MERS-CoV S, M and E proteins. Both IgG and F(ab’)(2) efficiently neutralized MERS-CoV replication in tissue culture. Passive transfer of equine immune antibodies significantly reduced virus titers and accelerated virus clearance from the lungs of MERS-CoV infected mice. Our data show that horses immunized with MERS-CoV VLPs can serve as a primary source of protective F(ab’)(2) for potential use in the prophylactic or therapeutic treatment of exposed or infected patients.


id: cord-264308-y6xuxj16
author: Liu, Rui
date: 2015-05-26
txt: ./txt/cord-264308-y6xuxj16.txt
cache: ./cache/cord-264308-y6xuxj16.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S016635421500128X
doi: 10.1016/j.antiviral.2015.05.008
summary:
  In this study, we established an ex vivo model using mouse lung slices to evaluate both antiviral and anti-inflammatory agents against influenza virus infection. Our results suggested that mouse lung slices provide a robust, convenient and cost-efficient model for the assessment of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. Our results showed that the lung slice model provides a robust, convenient and cost-economical method for the screening and evaluation of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. To meet the goal of this study in the establishment of an ex vivo mouse slice model for the screening and evaluation of both antiviral and anti-inflammatory drugs against influenza infection in one assay, ensuring that the ex vivo model has similar patterns in influenza-induced cytokine and chemokine responses is critical.

title:
  Mouse lung slices: An ex vivo model for the evaluation of antiviral and anti-inflammatory agents against influenza viruses

abstract:
  The influenza A virus is notoriously known for its ability to cause recurrent epidemics and global pandemics. Antiviral therapy is effective when treatment is initiated within 48 h of symptom onset, and delaying treatment beyond this time frame is associated with decreased efficacy. Research on anti-inflammatory therapy to ameliorate influenza-induced inflammation is currently underway and seems important to the impact on the clinical outcome. Both antiviral and anti-inflammatory drugs with novel mechanisms of action are urgently needed. Current methods for evaluating the efficacy of anti-influenza drugs rely mostly on transformed cells and animals. Transformed cell models are distantly related to physiological and pathological conditions. Although animals are the best choices for preclinical drug testing, they are not time- or cost-efficient. In this study, we established an ex vivo model using mouse lung slices to evaluate both antiviral and anti-inflammatory agents against influenza virus infection. Both influenza virus PR8 (H1N1) and A/Human/Hubei/3/2005 (H3N2) can replicate efficiently in mouse lung slices and trigger significant cytokine and chemokine responses. The induction of selected cytokines and chemokines were found to have a positive correlation between ex vivo and in vivo experiments, suggesting that the ex vivo cultured lung slices may closely resemble the lung functionally in an in vivo configuration when challenged by influenza virus. Furthermore, a set of agents with known antiviral and/or anti-inflammatory activities were tested to validate the ex vivo model. Our results suggested that mouse lung slices provide a robust, convenient and cost-efficient model for the assessment of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. This ex vivo model may predict the efficacy of drug candidates’ antiviral and anti-inflammatory activities in vivo.


id: cord-264488-989t9ld1
title: Inhibition of hepatitis B virus replication by ligand-mediated activation of RNase L
author: Park, Il-Hyun
date: 2014-02-06
txt: ./txt/cord-264488-989t9ld1.txt
cache: ./cache/cord-264488-989t9ld1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24509240/
doi: 10.1016/j.antiviral.2014.01.021
summary:
  In the present study, the potential antiviral activity of RNase L against hepatitis B virus (HBV) was explored utilizing the recently reported infection protocol based on human hepatoma HepG2 cells stably complemented with the virus entry factor NTCP. These results suggest that HBV replication can be regulated through interferon-mediated RNA decay pathways and that activation of these host antiviral factors may represent a novel therapeutic strategy for HBV infection. Our data indicate that ligand-mediated activation of these enzymes results in a marked inhibition of HBV replication in both infected and transfected cells. With the newly established HepG2-NTCP cell culture system, which permits HBV infection, we showed that viral gene expression and replication can be profoundly reduced by 2-5Aor poly(I:C)-mediated activation of RNase L. In HBV1.2-transfected Huh-7 cells, it was further confirmed that this type of inhibition occurred mostly through viral RNA degradation via the ribonuclease function of RNase L.

abstract:
  RNase L is a cellular endoribonuclease that is activated by 2′,5′-linked oligoadenylates (2–5A), which are unique and specific ligands synthesized by a family of interferon-inducible, dsRNA-activated enzymes named oligoadenylate synthetases. In the typical antiviral pathway, activated RNase L degrades viral and cellular RNAs, thus limiting viral replication and spread. Although the antiviral activity of RNase L has been demonstrated for several RNA viruses, there is little evidence regarding its role against DNA viruses. In the present study, the potential antiviral activity of RNase L against hepatitis B virus (HBV) was explored utilizing the recently reported infection protocol based on human hepatoma HepG2 cells stably complemented with the virus entry factor NTCP. Viral replication and expression in this cell type was markedly inhibited by poly(I:C)- or 2–5A-mediated activation of RNase L; however, the inhibition was significantly reversed by RNase L knockdown. Further analysis in HBV1.2-transfected Huh-7 hepatoma cells indicated that the antiviral activity of RNase L depends on its ribonuclease function. We also provide evidence for the specific roles of OAS family members in this process. These results suggest that HBV replication can be regulated through interferon-mediated RNA decay pathways and that activation of these host antiviral factors may represent a novel therapeutic strategy for HBV infection.


id: cord-266520-n439dwcx
author: Levanova, Alesia A.
date: 2020-08-13
txt: ./txt/cord-266520-n439dwcx.txt
cache: ./cache/cord-266520-n439dwcx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32798603/
doi: 10.1016/j.antiviral.2020.104916
summary:
  The antiviral efficacy of the 2''-F-siRNA swarms and the elicited cellular innate responses did not correlate suggesting that innate immunity pathways do not significantly contribute to the observed enhanced antiviral activity of the modified siRNAs. The results support further applications of enzymatically produced siRNA molecules with incorporated adenosine nucleotides, carrying fluoro-modification on ribose C2'' position, for further antiviral studies in vitro and in vivo. We have previously generated three antiviral siRNA swarms against herpes simplex virus type 1 (HSV-1) mRNAs encoding essential viral proteins, including glycoprotein B (UL27), the infected cell protein 8 (ICP8; UL29), and ICP27 (UL54) (Romanovskaya et al., 2012; Paavilainen et al., 2016) . The siRNA swarm targeting mRNA of HSV single-stranded DNA binding protein ICP8, encoded by the UL29 gene, harbors a most pronounced antiviral effect (Paavilainen et al., 2016) and induces only minimal non-specific cellular responses (Romanovskaya et al., 2012) .

title:
  Enzymatically synthesized 2''-fluoro-modified Dicer-substrate siRNA swarms against herpes simplex virus demonstrate enhanced antiviral efficacy and low cytotoxicity

abstract:
  Chemical modifications of small interfering (si)RNAs are used to enhance their stability and potency, and to reduce possible off-target effects, including immunogenicity. We have earlier introduced highly effective antiviral siRNA swarms against herpes simplex virus (HSV), targeting 653 bp of the essential UL29 viral gene. Here, we report a method for enzymatic production and antiviral use of 2’-fluoro-modified siRNA swarms. Utilizing the RNA-dependent RNA polymerase from bacteriophage phi6, we produced 2’-F-siRNA swarms containing either all or a fraction of modified adenosine, cytidine or uridine residues in the antisense strand of the UL29 target. The siRNA containing modified pyrimidines demonstrated high resistance to RNase A and the antiviral potency of all the UL29-specific 2’-F-siRNA swarms was 100-fold in comparison with the unmodified counterpart, without additional cytotoxicity. Modest stimulation of innate immunity signaling, including induced expression of both type I and type III interferons, as well as interferon-stimulated gene 54, by 2’-F-cytidine and 2’-F-uridine modified siRNA swarms occurred at early time points after transfection while the 2’-F-adenosine-containing siRNA was similar to the unmodified antiviral siRNA swarm in this respect. The antiviral efficacy of the 2’-F-siRNA swarms and the elicited cellular innate responses did not correlate suggesting that innate immunity pathways do not significantly contribute to the observed enhanced antiviral activity of the modified siRNAs. The results support further applications of enzymatically produced siRNA molecules with incorporated adenosine nucleotides, carrying fluoro-modification on ribose C2’ position, for further antiviral studies in vitro and in vivo.


id: cord-270364-lsfmcj5c
title: Antiseptic properties of two calix[4]arenes derivatives on the human coronavirus 229E()
author: Geller, C.
date: 2010-09-18
txt: ./txt/cord-270364-lsfmcj5c.txt
cache: ./cache/cord-270364-lsfmcj5c.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2010.09.009
doi: 10.1016/j.antiviral.2010.09.009
summary:
  Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4 log 10 reduction in viral titer after 5 min of contact with 10 −3 mol L −1 solutions of C[4]S-BTZ and chlorhexidine, respectively. Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4 log 10 reduction in viral titer after 5 min of contact with 10 −3 mol L −1 solutions of C[4]S-BTZ and chlorhexidine, respectively.

abstract:
  Facing the lack in specific antiviral treatment, it is necessary to develop new means of prevention. In the case of the Coronaviridae this family is now recognized as including potent human pathogens causing upper and lower respiratory tract infections as well as nosocomial ones. Within the purpose of developing new antiseptics molecules, the antiseptic virucidal activity of two calix[4]arene derivatives, the tetra-para-sulfonato-calix[4]arene (C[4]S) and the 1,3-bis(bithiazolyl)-tetra-para-sulfonato-calix[4]arene (C[4]S-BTZ) were evaluated toward the human coronavirus 229E (HCoV 229E). Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4 log(10) reduction in viral titer after 5 min of contact with 10(−3) mol L(−1) solutions of C[4]S-BTZ and chlorhexidine, respectively. Thus, the C[4]S-BTZ appeared as a promising virucidal (antiseptic) molecule.


id: cord-270498-hh6h50t2
author: Tseng, Chin-Kai
date: 2017-09-19
txt: ./txt/cord-270498-hh6h50t2.txt
cache: ./cache/cord-270498-hh6h50t2.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2017.09.010
doi: 10.1016/j.antiviral.2017.09.010
summary:
  Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. In this study, our data revealed that celastrol significantly inhibits HCV replication, and that the anti-HCV effect of celastrol was attenuated by the HO-1 specific inhibitor tin mesoporphyrin (SnMP) or HO-1 gene expression silencing. Celastrol-mediated HO-1 induction contributed to the anti-HCV action through inducing antiviral IFN response and inhibiting HCV NS3 protease activity. As shown in Fig. 7B , HO-1 RNA expression levels were induced by celastrol compared with non-celastrol treated cells and the JNK inhibitor SP600125 significantly reduced the HO-1 inductive effect of celastrol. In the present study, we found that a natural product celastrol could effectively inhibit HCV NS3/4A protease activity and enhance IFN-mediated antiviral gene expression through HO-1 induction (Figs.

title:
  Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells

abstract:
  BACKGROUND AND PURPOSE: Celastrol, a quinone methide triterpene isolated from the root extracts of Tripterygium wilfordii, can greatly induce the gene expression activity of heme oxygenase-1 (HO-1) to achieve disease prevention and control. HO-1 induction was recently shown to result in anti-HCV activity by inducing type I interferon and inhibiting hepatitis C virus (HCV) NS3/4A protease activity. The aim of the present study is to evaluate the anti-HCV activity of celastrol and characterize its mechanism of inhibition. METHODS: The anti-HCV activity of celastrol was evaluated using the HCV subgenomic replicon and HCVcc infection systems. The anti-HCV mechanism of celastrol targeting HO-1 expression was clarified using specific inhibitors against several signaling pathways. The transcriptional regulation of celastrol on target gene expression was determined using promoter-based reporter activity assay. The synergistic effect of celastrol and a numbers of clinically used anti-HCV drugs was determined via a drug combination assay. RESULTS: Celastrol inhibited HCV replication in both the HCV subgenomic and HCVcc infection systems with EC50 values of 0.37 ± 0.022 and 0.43 ± 0.019 μM, respectively. Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. JNK mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2) were confirmed to be involved in the inductive effect of celastrol on HO-1 expression. Celastrol exhibited synergistic effects in combination with interferon-alpha, the NS5A inhibitor daclatasvir, and the NS5B inhibitor sofosbuvir. CONCLUSION: Celastrol can serve as a potential supplement for blocking HCV replication. Targeting the JNK/Nrf2/HO-1 axis presents a promising strategy against HCV infection.


id: cord-271638-0wsyl7vk
author: Li, Wenmiao
date: 2020-03-09
txt: ./txt/cord-271638-0wsyl7vk.txt
cache: ./cache/cord-271638-0wsyl7vk.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354219305674
doi: 10.1016/j.antiviral.2020.104714
summary:
  Therefore, the natural dietary flavonoid myricetin has potential to be developed into a novel anti-HSV agent targeting both virus gD protein and cellular EGFR/PI3K/Akt pathway. As shown in Fig. 2C and E, myricetin treatment (20 μM) during adsorption significantly decreased the fluorescence of ICP5 protein on cell surface, compared to that in non-treated virus control cells, suggesting that myricetin may block virus adsorption process of HSV. As shown in Fig. 3A , in HSV-2 (MOI = 3.0) infected Vero cells, obvious syncytia with multinuclear cells were observed in non-treated virus control group (HSV-2) at 7 h p.i. However, treatment with myricetin (30, 15 μM) during 5-7 h p.i. markedly blocked syncytium formation only with a limited number of small syncytia, suggesting that myricetin may inhibit HSV-induced cell fusion. However, myricetin (2.5, 5, 10, 20 μM) treatment did not significantly influence the total expression levels of EGFR, PI3K and Akt proteins in HSV-2 infected Vero cells (Fig. 4G and H) .

title:
  Inhibition of herpes simplex virus by myricetin through targeting viral gD protein and cellular EGFR/PI3K/Akt pathway

abstract:
  Myricetin, a common dietary flavonoid, was reported to possess many different biological activities such as anti-oxidant, anti-inflammatory, and antiviral effects. In this study, we explored the anti-HSV effects and mechanisms of myricetin both in vitro and in vivo. The results showed that myricetin possessed anti-HSV-1 and HSV-2 activities with very low toxicity, superior to the effects of acyclovir. Myricetin may block HSV infection through direct interaction with virus gD protein to interfere with virus adsorption and membrane fusion, which was different from the nucleoside analogues such as acyclovir. Myricetin also down-regulate the cellular EGFR/PI3K/Akt signaling pathway to further inhibit HSV infection and its subsequent replication. Most importantly, intraperitoneal therapy of myricetin markedly improved mice survival and reduced virus titers in both lungs and spinal cord. Therefore, the natural dietary flavonoid myricetin has potential to be developed into a novel anti-HSV agent targeting both virus gD protein and cellular EGFR/PI3K/Akt pathway.


id: cord-275624-o5545c1x
author: Tai, Wanbo
date: 2020-05-13
txt: ./txt/cord-275624-o5545c1x.txt
cache: ./cache/cord-275624-o5545c1x.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220302345?v=s5
doi: 10.1016/j.antiviral.2020.104820
summary:
  Here, we constructed a series of SARS-CoV RBD mutant proteins based on the 176 interaction between the RBD and viral receptor (Li et al., 2005) , and performed an 177 ELISA to test binding ability of the above mAbs to these mutant proteins. In addition, control mAb 33G4 only blocked SARS-CoV 201 RBD, but not SARS-CoV-2 RBD, binding to the ACE2 receptor (Fig. 4B, C) , partially 202 explaining why this mAb did not neutralize SARS-CoV-2 infection. 203 Moreover, the two cross-neutralizing mAbs, 18F3 and 7B11, respectively recognized 227 two conserved, as well as several non-conserved, neutralizing epitopes on the RBDs of 228 SARS-CoV and SARS-CoV-2. 318 Characterization of the receptor-binding domain (RBD) of 2019 novel 319 coronavirus: implication for development of RBD protein as a viral attachment 320 inhibitor and vaccine (B) Inhibition of SARS-CoV RBD-specific mAbs for 411 the binding of SARS-CoV or SARS-CoV-2 RBD to ACE2 receptor by flow 412 cytometry analysis.

title:
  Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2

abstract:
  SARS-CoV-2-caused COVID-19 cases are growing globally, calling for developing effective therapeutics to control the current pandemic. SARS-CoV-2 and SARS-CoV recognize angiotensin-converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Here, we identified six SARS-CoV RBD-specific neutralizing monoclonal antibodies (nAbs) that cross-reacted with SARS-CoV-2 RBD, two of which, 18F3 and 7B11, neutralized SARS-CoV-2 infection. 18F3 recognized conserved epitopes on SARS-CoV and SARS-CoV-2 RBDs, whereas 7B11 recognized epitopes on SARS-CoV RBD not fully conserved in SARS-CoV-2 RBD. The 18F3-recognizing epitopes on RBD did not overlap with the ACE2-binding sites, whereas those recognized by 7B11 were close to the ACE2-binding sites, explaining why 7B11 could, but 18F3 could not, block SARS-CoV or SARS-CoV-2 RBD binding to ACE2 receptor. Our study provides an alternative approach to prevent SARS-CoV-2 infection using anti-SARS-CoV nAbs.


id: cord-277443-mv7sk5aa
author: Kumaki, Yohichi
date: 2016-12-09
txt: ./txt/cord-277443-mv7sk5aa.txt
cache: ./cache/cord-277443-mv7sk5aa.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27956136/
doi: 10.1016/j.antiviral.2016.12.007
summary:
  Hiltonol(®) at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). In other studies, treatment with an interferon inducer, polyriboinosinicpolyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose (poly IC:LC), given by the intranasal route, was effective in protecting mice against a lethal infection with mouseadapted SARS-CoV and reduced viral lung titers (Kumaki et al., 2010) . These treated, SARS-CoVinfected mice receiving the various Hiltonol ® dosing regimens were also significantly protected against weight loss due to virus infection (Table 1 , p < 0.05-p<0.001) from days 0e3 post virus exposure when the greatest weight loss occurred in this mouse model.

title:
  Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol(®) (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model

abstract:
  Hiltonol(®), (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol(®) was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol(®) at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol(®) treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol(®) at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol(®) treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol(®) was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol(®) was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol(®) treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol(®) is considered for possible clinical use.


id: cord-277860-vzyrcmu4
author: Pizzorno, Andrés
date: 2020-07-15
txt: ./txt/cord-277860-vzyrcmu4.txt
cache: ./cache/cord-277860-vzyrcmu4.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220302928?v=s5
doi: 10.1016/j.antiviral.2020.104878
summary:
  In vitro evaluation of antiviral activity of single and combined repurposable drugs 1 against SARS-CoV-2 2 3 Authors: Andrés Pizzorno a , Blandine Padey a,b , Julia Dubois a , Thomas Julien a,c , Aurélien 4 Traversier a , Victoria Dulière a,c , Pauline Brun a,c , Bruno Lina a,d , Manuel Rosa-Calatrava a,c* † , 5 Olivier Terrier a* † 6 7 Author affiliations: Abstract: 27 In response to the current pandemic caused by the novel SARS-CoV-2, identifying and 28 validating effective therapeutic strategies is more than ever necessary. We evaluated the in 29 vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum 30 activities, together with drugs that are currently under evaluation in clinical trials for COVID-31 19 patients. We evaluated the in 29 vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum 30 activities, together with drugs that are currently under evaluation in clinical trials for COVID-31 19 patients.

title:
  In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2

abstract:
  In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.


id: cord-278876-il7g78w1
title: 2016 International meeting of the Global Virus Network
author: Akkina, Ramesh
date: 2017-03-16
txt: ./txt/cord-278876-il7g78w1.txt
cache: ./cache/cord-278876-il7g78w1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2017.03.005
doi: 10.1016/j.antiviral.2017.03.005
summary:
  This report highlights the accomplishments of GVN researchers in many priority areas of medical virology, including the current Zika epidemic, infections by human papillomavirus, influenza, Ebola, Lassa, dengue, HIV, hepatitis C, and chikungunya viruses, and the development of improved diagnostics and new vaccines. This meeting report highlights accomplishments of GVN researchers in many priority areas of human virology, including the current Zika epidemic, infections by human papillomavirus, influenza, Ebola, Lassa, dengue, HIV, hepatitis C and chikungunya viruses, and the development of improved diagnostics and new vaccines. The main objectives of the meeting were to present and discuss current findings in medical virology, including advances in research on HIV vaccines and other important retroviruses; provide a framework to encourage collaborations among world experts; and address the GVN''s annual strategy for continued development. Hideki Hasegawa, a GVN center director at the National Institute of Infectious Diseases in Tokyo, explained that secretory IgA antibodies on mucosal surfaces play an important role in protection against influenza virus infection.

abstract:
  The Global Virus Network (GVN) was established in 2011 in order to strengthen research and responses to current viral causes of human disease and to prepare against new viral pandemic threats. There are now 38 GVN Centers of Excellence and 6 Affiliate laboratories in 24 countries. GVN scientists meet annually to learn about each other's current research, address collaborative priorities and plan future programs. The 2016 meeting was held from October 23–25 in Hokkaido, Japan, in partnership with the Japanese Society for Virology, the National Institute of Infectious Diseases of Japan and the Research Center for Zoonosis Control of Hokkaido University. This report highlights the accomplishments of GVN researchers in many priority areas of medical virology, including the current Zika epidemic, infections by human papillomavirus, influenza, Ebola, Lassa, dengue, HIV, hepatitis C, and chikungunya viruses, and the development of improved diagnostics and new vaccines.


id: cord-281069-m638nyt0
author: Hong, Wei
date: 2013-12-04
txt: ./txt/cord-281069-m638nyt0.txt
cache: ./cache/cord-281069-m638nyt0.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354213003550
doi: 10.1016/j.antiviral.2013.11.013
summary:
  Both Hp1036 and Hp1239 peptides exhibited potent virucidal activities against HSV-1 (EC(50) = 0.43 ± 0.09 and 0.41 ± 0.06 μM, respectively) and effective inhibitory effects when added at the viral attachment (EC(50) = 2.87 ± 0.16 and 5.73 ± 0.61 μM, respectively), entry (EC(50) = 4.29 ± 0.35 and 4.32 ± 0.47 μM, respectively) and postentry (EC(50) = 7.86 ± 0.80 and 8.41 ± 0.73 μM, respectively) steps. An extended peptide from bovine, indolicidin, showed a direct inactivation effect on cell-free HSV-1 virons by targeting viral membrane/ glycoprotein (Albiol Matanic and Castilla, 2004 Natural AMPs from scorpion venoms have attracted much attention due to their anti-viral bioactivities. To determine whether Hp1036 and Hp1239 could inhibit HSV-1 infection or replication in Vero cells, 10 lM of each peptide was added to the virus or cells at different times relative to incubation (Fig. 3A) . Various concentrations of peptides were added to Vero cells 1 h before HSV-1 infection and the inhibitory effects were determined by plaque assay.

title:
  Inhibitory activity and mechanism of two scorpion venom peptides against herpes simplex virus type 1

abstract:
  Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen that causes severe diseases, but there are not effective and safe drugs in clinical therapy besides acyclovir (ACV) and related nucleoside analogs. In this study, two new venom peptides from the scorpion Heterometrus petersii were identified with effective inhibitory effect on HSV-1 infection in vitro. Both Hp1036 and Hp1239 peptides exhibited potent virucidal activities against HSV-1 (EC(50) = 0.43 ± 0.09 and 0.41 ± 0.06 μM, respectively) and effective inhibitory effects when added at the viral attachment (EC(50) = 2.87 ± 0.16 and 5.73 ± 0.61 μM, respectively), entry (EC(50) = 4.29 ± 0.35 and 4.32 ± 0.47 μM, respectively) and postentry (EC(50) = 7.86 ± 0.80 and 8.41 ± 0.73 μM, respectively) steps. Both Hp1036 and Hp1239 peptides adopted α-helix structure in approximate membrane environment and resulted in the destruction of the viral morphology. Moreover, Hp1036 and Hp1239 peptides entered Vero cells and reduced the intracellular viral infectivity. Taken together, Hp1036 and Hp1239 peptides are two anti-viral peptides with effective inhibitory effect on multiple steps of HSV-1 life cycle and therefore are good candidate for development as virucides.


id: cord-281385-oxohdfpu
title: Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine
author: Noble, Christian G.
date: 2014-09-19
txt: ./txt/cord-281385-oxohdfpu.txt
cache: ./cache/cord-281385-oxohdfpu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25241250/
doi: 10.1016/j.antiviral.2014.09.003
summary:
  Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the methyl donor molecule that co-purifies with the enzymes. The SAM-depleted and SAM-containing MTases exhibited comparable enzymatic activities (N-7 MTase, 2 0 -O MTase, and covalent GMP-MTase complex formation the natural product Sinefungin, showing that this is a viable approach to identify novel small molecules that bind to the same pocket. This conclusion was supported by two complementary structural and functional approaches: (i) the crystal structure unequivocally shows that absence of SAM does not affect the overall conformation of DENV MTase, including the SAM-binding pocket; (ii) depletion of SAM from the recombinant MTase did not change the activities of cap methylations and GMP-MTase complex formation. Structural and functional analysis of methylation and 5 0 -RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5

abstract:
  Flavivirus methyltransferase is a genetically-validated antiviral target. Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the methyl donor molecule that co-purifies with the enzymes. This raises a possibility that SAM is an integral structural component required for the folding of dengue virus (DENV) methyltransferase. Here we exclude this possibility by solving the crystal structure of DENV methyltransferase without SAM. The SAM ligand was removed from the enzyme through a urea-mediated denaturation-and-renaturation protocol. The crystal structure of the SAM-depleted enzyme exhibits a vacant SAM-binding pocket, with a conformation identical to that of the SAM-enzyme co-crystal structure. Functionally, equivalent enzymatic activities (N-7 methylation, 2′-O methylation, and GMP-enzyme complex formation) were detected for the SAM-depleted and SAM-containing recombinant proteins. These results clearly indicate that the SAM molecule is not an essential component for the correct folding of DENV methyltransferase. Furthermore, the results imply a potential antiviral approach to search for inhibitors that can bind to the SAM-binding pocket and compete against SAM binding. To demonstrate this potential, we have soaked crystals of DENV methyltransferase without a bound SAM with the natural product Sinefungin and show that preformed crystals are capable of binding ligands in this pocket.


id: cord-283739-p7b4mtbl
author: Theerawatanasirikul, Sirin
date: 2020-09-07
txt: ./txt/cord-283739-p7b4mtbl.txt
cache: ./cache/cord-283739-p7b4mtbl.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220303417?v=s5
doi: 10.1016/j.antiviral.2020.104927
summary:
  We investigated the potential drug-liked compounds and their inhibitory interaction on the 3CL(pro) active sites of CoVs by the structural-bases virtual screening. Evaluation of antiviral activity using cell-based assay showed that NSC629301 and NSC71097 could strongly inhibit the cytopathic effect and also reduced replication of FIPV in CRFK cells in all examined conditions with the low range of EC(50) (6.11 ± 1.90 to 7.75 ± 0.48 μM and 1.99 ± 0.30 to 4.03 ± 0.60 μM, respectively), less than those of ribavirin and lopinavir. According to the FIPV 3CL pro structurral based study, we determined if the candidate 293 compounds that could bind to the active site and inhibited the protease activity still actively 294 Cys144 and His41, the active residues of FIPV 3CL pro , formed the π-alkyl interaction 352 and hydrogen bond to the compounds, respectively.

title:
  Structural-based virtual screening and in vitro assays for small molecules inhibiting the feline coronavirus 3CL protease as a surrogate platform for coronaviruses

abstract:
  Feline infectious peritonitis (FIP) which is caused by feline infectious peritonitis virus (FIPV), a variant of feline coronavirus (FCoV), is a member of family Coronaviridae, together with severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. So far, neither effective vaccines nor approved antiviral therapeutics are currently available for the treatment of FIPV infection. Both human and animal CoVs shares similar functional proteins, particularly the 3CL protease (3CL(pro)), which plays the pivotal role on viral replication. We investigated the potential drug-liked compounds and their inhibitory interaction on the 3CL(pro) active sites of CoVs by the structural-bases virtual screening. Fluorescence resonance energy transfer (FRET) assay revealed that three out of twenty-eight compounds could hamper FIPV 3CL(pro) activities with IC(50) of 3.57 ± 0.36 μM to 25.90 ± 1.40 μM, and Ki values of 2.04 ± 0.08 to 15.21 ± 1.76 μM, respectively. Evaluation of antiviral activity using cell-based assay showed that NSC629301 and NSC71097 could strongly inhibit the cytopathic effect and also reduced replication of FIPV in CRFK cells in all examined conditions with the low range of EC(50) (6.11 ± 1.90 to 7.75 ± 0.48 μM and 1.99 ± 0.30 to 4.03 ± 0.60 μM, respectively), less than those of ribavirin and lopinavir. Analysis of FIPV 3CL(pro)-ligand interaction demonstrated that the selected compounds reacted to the crucial residues (His41 and Cys144) of catalytic dyad. Our investigations provide a fundamental knowledge for the further development of antiviral agents and increase the number of anti-CoV agent pools for feline coronavirus and other related CoVs.


id: cord-284076-087oltss
author: Patel, Deendayal
date: 2007-10-04
txt: ./txt/cord-284076-087oltss.txt
cache: ./cache/cord-284076-087oltss.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/17959259/
doi: 10.1016/j.antiviral.2007.09.002
summary:
  Of 12 peptide-conjugated PMO (PPMO), four were found to be highly effective at inhibiting PRRSV replication in cell culture in a dose-dependant and sequence-specific manner. In a previous study (Zhang et al., 2006) , we tested six PPMO and found one of them (5UP1), designed to target the 5 terminal region of the PRRSV genome, to be a highly effective inhibitor of PRRSV replication in a sequence-specific and dose-dependent manner. Confirmation of the CPE observations and PRRSV yield titration was obtained by IFA on CRL11171 cells after virus inoculation and PPMO treatment (Fig. 2B ). demonstrated that PPMO generated little cytotoxicity in both CRL11171 and PAM cells, further indicating that the suppression of virus replication observed in the antiviral experiments above was due to sequence-specific effects. Treatment of cells with PPMO 5UP2 or 5HP led to suppression of PRRSV replication of all North American strains, producing virus yields not detectable (ND) in this assay.

title:
  Peptide-conjugated morpholino oligomers inhibit porcine reproductive and respiratory syndrome virus replication

abstract:
  Porcine reproductive and respiratory syndrome (PRRS) has been devastating the global swine industry for more than a decade, and current strategies to control PRRS are inadequate. In this study we characterized the inhibition of PRRS virus (PRRSV) replication by antisense phosphorodiamidate morpholino oligomers (PMO). Of 12 peptide-conjugated PMO (PPMO), four were found to be highly effective at inhibiting PRRSV replication in cell culture in a dose-dependant and sequence-specific manner. PPMO 5UP2 and 5HP are complementary to sequence in the 5′ end of the PRRSV genome, and 6P1 and 7P1 to sequence in the translation initiation regions of ORF6 and ORF7, respectively. Treatment of cells with 5UP2 or 5HP caused a 4.5 log(10) reduction in PRRSV yield, compared to a control PPMO. Combination of 6P1 and 7P1 led to higher level reduction than 6P1 or 7P1 alone. 5UP2, 5HP, and a combination of 6P1 and 7P1 inhibited PRRSV replication in porcine alveolar macrophages and protected the cells from PRRSV-induced cytopathic effect. Northern blot and real-time RT-PCR results demonstrated that the effective PPMO led to a reduction of PRRSV RNA level. 5UP2 and 5HP inhibited virus replication of 10 other strains of PRRSV. Results from this study suggest potential applications of PPMO for PRRS control.


id: cord-284655-zemns7wd
author: Calvo-Pinilla, Eva
date: 2015-01-30
txt: ./txt/cord-284655-zemns7wd.txt
cache: ./cache/cord-284655-zemns7wd.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354215000108
doi: 10.1016/j.antiviral.2015.01.009
summary:
  Previous studies show that a recombinant modified vaccinia Ankara (MVA) virus expressing VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against challenge. Follow up experiments indicated that passive transfer of antiserum, from MVA-VP2 immune donors to recipient mice 1 h before challenge, conferred complete clinical protection and significantly reduced viraemia. In this paper, follow-up studies investigating the relative contribution of humoral and cell-mediated immunity to the protection conferred by MVA-VP2 vaccination, using passive immunisation of naïve recipient IFNAR À/À mice with splenocytes or antiserum from MVA-VP2 vaccinated mice, are described. Vaccination of mice with a modified Vaccinia Ankara (MVA) virus expressing the African horse sickness virus (AHSV) capsid protein VP2 induces virus neutralising antibodies that confer protection against AHSV upon passive immunisation

title:
  Antiserum from mice vaccinated with modified vaccinia Ankara virus expressing African horse sickness virus (AHSV) VP2 provides protection when it is administered 48 h before, or 48 h after challenge

abstract:
  Previous studies show that a recombinant modified vaccinia Ankara (MVA) virus expressing VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against challenge. Follow up experiments indicated that passive transfer of antiserum, from MVA-VP2 immune donors to recipient mice 1 h before challenge, conferred complete clinical protection and significantly reduced viraemia. These studies have been extended to determine the protective effect of MVA-VP2 vaccine-induced antiserum, when administered 48 h before, or 48 h after challenge. In addition, passive transfer of splenocytes was undertaken to assess if they confer any degree of immunity to immunologically naïve recipient mice. Thus, antisera and splenocytes were collected from groups of mice that had been vaccinated with MVA-VP2, or wild type MVA (MVA-wt), for passive immunisation of recipient mice. The latter were subsequently challenged with AHSV-4 (together with appropriate vaccinated or unvaccinated control animals) and protection was assessed by comparing clinical signs, lethality and viraemia between treated and control groups. All antiserum recipients showed high protection against disease (100% survival rates even in mice that were immunised 48 h after challenge) and statistically significant reduction or viraemia in comparison with the control groups. The mouse group receiving splenocytes from MVA-VP2 vaccinates, showed only a 40% survival rate, with a small reduction in viraemia, compared to those mice that had received splenocytes from MVA-wt vaccinates. These results confirm the primarily humoral nature of protective immunity conferred by MVA-VP2 vaccination and show the potential of administering MVA-VP2 specific antiserum as an emergency treatment for AHSV.


id: cord-285505-8norumv6
title: Meeting report: 27th International conference on antiviral research, in Raleigh, NC, USA
author: Vere Hodge, R. Anthony
date: 2014-09-16
txt: ./txt/cord-285505-8norumv6.txt
cache: ./cache/cord-285505-8norumv6.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354214002460
doi: 10.1016/j.antiviral.2014.08.009
summary:
  The focus of John''s presentation was on the research conducted in his own and his collaborators'' laboratories that ultimately led to the invention of three compounds which were discovered to have antiviral activity against human cytomegalovirus (HCMV) and which later entered clinical trials: BDCRB pyranoside (GW275175X) (Phase I), maribavir (Phases I, II and III) and cyclopropavir (Phase I). In monotherapy studies after oral dosing with TDF (300 mg) and TAF (25 mg), the plasma TFV AUC is reduced from 1920 to 268 ng.h/ml respectively whereas the reduction in HIV load from baseline is improved, from log 10 0.97 to log 10 1.46 copies/ml, respectively, reflecting the more efficient delivery of TAF to target cells and tissues. David Margolis, University of North Carolina, NC, USA In HIV-infected patients, there is a long-lasting reservoir of HIV in the form of integrated viral DNA in resting CD4+ memory cells of the host immune system.

abstract:
  The 27th International Conference on Antiviral Research (ICAR) was held in Raleigh, North Carolina, USA from May 12 to 16, 2014. This article summarizes the principal invited lectures. John Drach (Elion Award) described the early days of antiviral drugs and their novel modes of action. Piet Herdewijn (Holý Award) used evolutionary pressure to select DNA polymerases that accept nucleoside analogs. Replacing thymine by 5-chlorouracil led to the generation of a new form of Escherichia coli. Adrian Ray (Prusoff Award) demonstrated how prodrugs can markedly improve both the efficacy and safety of potential drugs. The keynote addresses, by David Margolis and Myron Cohen, tackled two emerging areas of HIV research, to find an HIV “cure” and to prevent HIV transmission, respectively. These topics were discussed further in other presentations – a cure seems to be a distant prospect but there are exciting developments for reducing HIV transmission. TDF-containing vaginal rings and GSK-744, as a long-lasting injection, offer great hope. There were three mini-symposia. Although therapy with TDF/FTC gives excellent control of HBV replication, there are only a few patients who achieve a functional cure. Myrcludex, an entry inhibitor, is active against both HBV and HDV. The recent progress with HBV replication in cell cultures has transformed the search for new antiviral compounds. The HBV capsid protein has been recognized as key player in HBV DNA synthesis. Unexpectedly, compounds which enhance capsid formation, markedly reduce HBV DNA synthesis. The development of BCX4430, which is active against Marburg and Ebola viruses, is of great current interest.


id: cord-285856-0sw3wt1i
author: Naesens, Lieve
date: 2009-02-05
txt: ./txt/cord-285856-0sw3wt1i.txt
cache: ./cache/cord-285856-0sw3wt1i.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2009.01.003
doi: 10.1016/j.antiviral.2009.01.003
summary:
  We here report on the chemical synthesis, anti-influenza virus activity and structure-activity relationship of novel glycopeptide compounds carrying a hydrophobic side chain on an aglycoristocetin backbone ( Fig. 1) . b HPLC conditions: instrument: Waters 600 with UV230nm detection; column: Lichrospher RP-8 (4 mm × 250 mm; 10 m); injection volume: 20 l (corresponding to 2 g compound); solvents: Table 2 , several asymmetric squaric diamides derived from aglycoristocetin exerted marked activity against influenza virus, the most potent compounds being the phenylbenzyl derivative 8e [average antiviral EC 50 : 0.4 M; selectivity index (SI), defined as the ratio of MCC to EC 50 : 50]; the hexanol deriva-tive 8a (EC 50 : 1 M; SI: 14) and the naphthyl derivative 8f (EC 50 : 1.4 M; SI: 10). With regard to the antiviral mode of action, time-of-addition studies suggested that 8e blocks the viral entry process, since optimal anti-influenza virus activity was obtained when the compound was added to MDCK cells 30 min prior to or simultaneously with virus infection.

title:
  Anti-influenza virus activity and structure–activity relationship of aglycoristocetin derivatives with cyclobutenedione carrying hydrophobic chains

abstract:
  Previous studies have demonstrated that glycopeptide compounds carrying hydrophobic substituents can have favorable pharmacological (i.e. antibacterial and antiviral) properties. We here report on the in vitro anti-influenza virus activity of aglycoristocetin derivatives containing hydrophobic side chain-substituted cyclobutenedione. The lead compound 8e displayed an antivirally effective concentration of 0.4 μM, which was consistent amongst influenza A/H1N1, A/H3N2 and B viruses, and a selectivity index ≥50. Structural analogues derived from aglycovancomycin were found to be inactive. The hydrophobic side chain was shown to be an important determinant of activity. The narrow structure–activity relationship and broad activity against several human influenza viruses suggest a highly conserved interaction site, which is presumably related to the influenza virus entry process. Compound 8e proved to be inactive against several unrelated RNA and DNA viruses, except for varicella-zoster virus, against which a favorable activity was noted.


id: cord-286103-cgky6ar6
title: Inhibition of measles virus and subacute sclerosing panencephalitis virus by RNA interference
author: Otaki, Momoko
date: 2006-02-13
txt: ./txt/cord-286103-cgky6ar6.txt
cache: ./cache/cord-286103-cgky6ar6.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354206000295
doi: 10.1016/j.antiviral.2006.01.009
summary:
  In this study, we adopted RNA interference (RNAi) strategy and examined whether small interfering RNAs (siRNAs) can be used to inhibit replication of MeV and SSPE virus. We report here that siRNAs targeted against L mRNA of MeV, either synthetic siRNAs or those generated by pcPUR + U6i-based expression plasmids, effectively and specifically inhibited replication of both MeV and SSPE virus without exhibiting any cytotoxic effect. We report here that siRNAs targeted against L mRNA of MeV, either synthetic ones or those generated by pcPUR + U6i-based expression plasmids, effectively inhibit replication of both MeV and SSPE virus. Indeed, we demonstrated in the present study that siRNAs targeted against selected portions of L mRNA of MeV, especially MV-L2 -L4 and -L5, either synthetic siRNAs or those expressed by pcPUR + U6i-based plasmids, effectively inhibited replication of both MeV and SSPE virus (Figs.

abstract:
  Subacute sclerosing panencephalitis (SSPE) is a rare, but fatal outcome of measles virus (MeV) infection. SSPE develops after prolonged persistence of mutated MeV called SSPE virus. Although a combination therapy using interferon and inosiplex or ribavirin appears to prolong survival time to some extent, there is currently no effective treatment to completely cure SSPE and a new treatment strategy is greatly needed. In this study, we adopted RNA interference (RNAi) strategy and examined whether small interfering RNAs (siRNAs) can be used to inhibit replication of MeV and SSPE virus. We report here that siRNAs targeted against L mRNA of MeV, either synthetic siRNAs or those generated by pcPUR + U6i-based expression plasmids, effectively and specifically inhibited replication of both MeV and SSPE virus without exhibiting any cytotoxic effect. The L protein of MeV is a major component of RNA-dependent RNA polymerase that is essential for viral RNA replication, and yet it is least abundant among all the MeV proteins expressed. Therefore, mRNA encoding the L protein would be a good target for RNAi strategy. The present results imply the possibility that our siRNAs against MeV L mRNA are among the potential candidates to be used to treat patients with SSPE.


id: cord-286831-ni7qfjk9
title: Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus
author: Choi, Hwa-Jung
date: 2008-11-06
txt: ./txt/cord-286831-ni7qfjk9.txt
cache: ./cache/cord-286831-ni7qfjk9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18992773/
doi: 10.1016/j.antiviral.2008.10.002
summary:
  Following this, 0.09 mL of diluted virus suspension of PEDV containing CCID 50 (50% cell culture infective dose) of the virus stock to produce a appropriate cytopathic effects within 2 days after infection and 0.01 mL of medium supplemented with typsin-EDTA containing an appropriate concentration of the compounds were added. Current antiviral drugs, natural compounds and flavonoids were further studied for their inhibitory effects on replication of the PEDV and cytotoxicity in Vero cells, among which ribavirin, tannic acid, coumarin and interferon-␣ exhibited the activities with IC 50 of 4.1, 47.4, 9 g/mL and 0.52 unit, respectively. A similar result was obtained in control infections with treated ribavirin (Fig. 1 ), but antiviral activity was shown to be lower than that of Q7R. Trials of ribavirin in this study showed that the drug had favorable effects on antiviral activity in Vero cells infected with PEDV.

abstract:
  Porcine epidemic diarrhea virus (PEDV) is the predominant cause of severe entero-pathogenic diarrhea in swine. The lack of effective therapeutical treatment underlines the importance of research for new antivirals. In this study, we identified Q7R, which actively inhibited PEDV replication with a 50% inhibitory concentration (IC(50)) of 0.014 μg/mL. The 50% cytotoxicity concentration (CC(50)) of Q7R was over 100 μg/mL and the derived therapeutic index was 7142. Several structural analogues of Q7R, quercetin, apigenin, luteolin and catechin, also showed moderate anti-PEDV activity. Antiviral drugs and natural compounds revealed ribavirin, interferon-α, coumarin and tannic acid have relative weaker efficacy compared to Q7R. Q7R did not directly interact with or inactivate PEDV particles and affect the initial stage of PEDV infection by interfering of PEDV replication. Also, the effectiveness of Q7R against the other two viruses (TGEV, PRCV) was lower compared to PEDV. Q7R could be considered as a lead compound for development of anti-PEDV drugs to may be used to during the early stage of PEDV replication and the structure-activity data of Q7R may usefully guideline to design other related antiviral agents.


id: cord-288146-xqxznv1r
author: Kohyama, Shunsuke
date: 2009-09-11
txt: ./txt/cord-288146-xqxznv1r.txt
cache: ./cache/cord-288146-xqxznv1r.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/19748524/
doi: 10.1016/j.antiviral.2009.09.004
summary:
  title: Efficient induction of cytotoxic T lymphocytes specific for severe acute respiratory syndrome (SARS)-associated coronavirus by immunization with surface-linked liposomal peptides derived from a non-structural polyprotein 1a As shown in Fig. 2 , significant numbers of IFN-␥-producing CD8 + T cells (p < 0.01) were detected in mice immunized with syngeneic cells pulsed with each of nine pp1aderived peptides including pp1a-2187, -2207, -2340, -2546, -2755, -2990, -3444, -3687, and -3709 , suggesting that these nine peptides may be HLA-A*0201-restricted CTL epitopes derived from SARS-CoV pp1a protein. After HHD mice were immunized once with one of the nine liposomal peptides, spleen cells of them were prepared, stimulated with a relevant synthetic peptide, and stained for their expression of surface CD8 and intracellular IFN-␥. In summary, we have identified seven HLA-A*0201-restricted CTL epitopes derived from pp1a protein of SARS-CoV using computational algorithms, HLA-A*0201 transgenic mice and the surface-linked liposomal peptide.

title:
  Efficient induction of cytotoxic T lymphocytes specific for severe acute respiratory syndrome (SARS)-associated coronavirus by immunization with surface-linked liposomal peptides derived from a non-structural polyprotein 1a

abstract:
  Spike and nucleocapsid are structural proteins of severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) and major targets for cytotoxic T lymphocytes (CTLs). In contrast, non-structural proteins encoded by two-thirds of viral genome are poorly characterized for cell-mediated immunity. We previously demonstrated that nucleocapsid-derived peptides chemically coupled to the surface of liposomes effectively elicited SARS-CoV-specific CTLs in mice. Here, we attempted to identify HLA-A*0201-restricted CTL epitopes derived from a non-structural polyprotein 1a (pp1a) of SARS-CoV, and investigated whether liposomal peptides derived from pp1a were effective for CTL induction. Out of 30 peptides predicted on computational algorithms, nine peptides could significantly induce interferon gamma (IFN-γ)-producing CD8(+) T cells in mice. These peptides were coupled to the surface of liposomes, and inoculated into mice. Six liposomal peptides effectively induced IFN-γ-producing CD8(+) T cells and seven liposomal peptides including the six peptides primed CTLs showing in vivo killing activities. Further, CTLs induced by the seven liposomal peptides lysed an HLA-A*0201 positive cell line expressing naturally processed, pp1a-derived peptides. Of note, one of the liposomal peptides induced high numbers of long-lasting memory CTLs. These data suggest that surface-linked liposomal peptides derived from pp1a might offer an efficient CTL-based vaccine against SARS.


id: cord-288337-sw7xjpbr
title: Edible bird''s nest extract inhibits influenza virus infection
author: Guo, Chao-Tan
date: 2006-03-03
txt: ./txt/cord-288337-sw7xjpbr.txt
cache: ./cache/cord-288337-sw7xjpbr.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354206000581
doi: 10.1016/j.antiviral.2006.02.005
summary:
  Five microliters of influenza virus suspension (500 ng protein) in 50 mM sodium acetate buffer (pH 5.5) containing two-fold serial dilution of the EBN extracts was stored at 37 • C for 30 min and then incubated with 5 l of 4 mM 2 -(4-methylumbelliferyl)-␣-d-N-acetylneuraminic acid (4-MU-Neu5Ac) (Sigma-Aldrich, St. Louis, MO) at 37 • C for 30 min. In order to check the reaction of EBN extract with influenza viruses, we used the human influenza virus strain A/Aichi/2/68 (H3N2), which bound to both sialyl ␣2-3 and ␣2-6 galactose linkages in salylglycoproteins and sialylglycolipids, and carried out an SDS-PAGE Western blotting assay to analyze the glycoprotein molecules. As shown in Fig. 2A , in case of no treatment with the pancreatic enzyme, neither the EBN extract from S1 nor that from S2 inhibited the hemagglutination of influenza A virus (strain A/Aichi/2/68) to human type O erythrocytes.

abstract:
  Edible bird's nest (EBN) is the nest of the swift that is made from its saliva. Although EBN has been widely used for enhancing immunocompetence, its antiviral efficacy has not been studied in detail. We found that EBN extract could strongly inhibit infection with influenza viruses in a host range-independent manner when it was hydrolyzed with Pancreatin F. Western blotting assay showed that the EBN extract bound to influenza virus. Furthermore, EBN extract could neutralize the infection of MDCK cells with influenza viruses and inhibit hemagglutination of influenza viruses to erythrocytes, but it could not inhibit the activity of influenza virus sialidase. Fluorometric HPLC indicated that the major molecular species of sialic acid in EBN is N-acetylneuraminic acid. The results suggest that EBN is a safe and valid natural source for the prevention of influenza viruses.


id: cord-291143-nkv1h3uh
author: Matyushenko, Victoria
date: 2020-06-22
txt: ./txt/cord-291143-nkv1h3uh.txt
cache: ./cache/cord-291143-nkv1h3uh.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220302783?v=s5
doi: 10.1016/j.antiviral.2020.104864
summary:
  title: Conserved T-cell epitopes of respiratory syncytial virus (RSV) delivered by recombinant live attenuated influenza vaccine viruses efficiently induce RSV-specific lung-localized memory T cells and augment influenza-specific resident memory T-cell responses Surprisingly, the CD69(+)CD103(+) influenza-specific CD8 Tem responses were augmented by the addition of RSV epitopes, possibly as a result of the local microenvironment formed by the RSV-specific memory T cells differentiating to T(RM) in the lungs of mice immunized with LAIV-RSV chimeric viruses. demonstrated that a booster immunization with M2 82 RSV epitope, delivered directly to the lungs by a recombinant influenza virus expressing this epitope, generated RSV-specific lung-localized memory CD8 T cells, which were associated with reduced immunopathology following RSV challenge (Schmidt et al., 2018) . However, significant levels of CD4 Tem cells, expressing both CD69 and CD103 markers associated with tissue residence, were identified in the lungs of mice immunized with either of the LAIV-RSV vaccine candidates (Fig.3B ).

title:
  Conserved T-cell epitopes of respiratory syncytial virus (RSV) delivered by recombinant live attenuated influenza vaccine viruses efficiently induce RSV-specific lung-localized memory T cells and augment influenza-specific resident memory T-cell responses

abstract:
  Respiratory syncytial virus (RSV) can cause recurrent infection in people because it does not stimulate a long-lived immunological memory. There is an urgent need to develop a safe and efficacious vaccine against RSV that would induce immunological memory without causing immunopathology following natural RSV infection. We have previously generated two recombinant live attenuated influenza vaccine (LAIV) viruses that encode immunodominant T-cell epitopes of RSV M2 protein in the neuraminidase or NS1 genes. These chimeric vaccines afforded protection against influenza and RSV infection in mice, without causing pulmonary eosinophilia or inflammatory RSV disease. The current study assessed the formation of influenza-specific and RSV-specific CD4 and CD8 T-cell responses in the lungs of mice, with special attention to the lung tissue-resident memory T cell subsets (T(RM)). The RSV epitopes did not affect influenza-specific CD4 effector memory T cell (Tem) levels in the lungs. The majority of these cells formed by LAIV or LAIV-RSV viruses had CD69(+)CD103(-) phenotype. Both LAIV+NA/RSV and LAIV+NS/RSV recombinant viruses induced significant levels of RSV M2(82) epitope-specific lung-localized CD8 Tem cells expressing both CD69 and CD103 T(RM) markers. Surprisingly, the CD69(+)CD103(+) influenza-specific CD8 Tem responses were augmented by the addition of RSV epitopes, possibly as a result of the local microenvironment formed by the RSV-specific memory T cells differentiating to T(RM) in the lungs of mice immunized with LAIV-RSV chimeric viruses. This study provides evidence that LAIV vector-based vaccination can induce robust lung-localized T-cell immunity to the inserted T-cell epitope of a foreign pathogen, without altering the immunogenicity of the viral vector itself.


id: cord-292830-gcfx1095
title: Novel activities of safe-in-human broad-spectrum antiviral agents
author: Ianevski, Aleksandr
date: 2018-04-23
txt: ./txt/cord-292830-gcfx1095.txt
cache: ./cache/cord-292830-gcfx1095.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29698664/
doi: 10.1016/j.antiviral.2018.04.016
summary:
  Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. Here, we hypothesised that some of the identified safe-in-human BSAs could possess novel antiviral activities and, therefore, could be used for treatment of many different viral infections. Fig. 1 shows BSAs and other approved antiviral drugs linked to viral and host targets through viruses they inhibit. Thus, we tested several known BSA agents against (−)ssRNA, (+) ssRNA, ssRNA-RT and dsDNA viruses and identified novel activities for dalbavancin against EV1, ezetimibe against ZIKV and HIV-1, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against RVFV. We identified novel antiviral activities for dalbavancin (against EV1), ezetimibe (against HIV-1 and ZIKV), azacitidine, cyclosporine, minocycline, oritavancin and ritonavir (against RVFV) (Fig. 4) .

abstract:
  According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.


id: cord-295421-zy517zwr
author: Xu, Jinfang
date: 2014-06-26
txt: ./txt/cord-295421-zy517zwr.txt
cache: ./cache/cord-295421-zy517zwr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24973762/
doi: 10.1016/j.antiviral.2014.06.008
summary:
  title: Swine interferon-induced transmembrane protein, sIFITM3, inhibits foot-and-mouth disease virus infection in vitro and in vivo Ectopic expression of sIFITM3 significantly inhibited non-enveloped foot-and-mouth disease virus (FMDV) infection in BHK-21 cells. Furthermore, sIFITM3 blocked FMDV infection at early steps in the virus life cycle by disrupting viral attachment to the host cell surface. Ectopic expression of sIFITM3 inhibited infection of non-enveloped FMDV in baby hamster kidney (BHK-21) cells by disrupting viral attachment, and this differs from human IFITM3 restriction on enveloped viruses. Two days post infection of the cell lines with viruses, plaque assay showed that BHK-sIFITM3 was less susceptible to infection by type O FMDV strains O/ES/ 2001, O/GD/2010, and O/AH/2010 than the control BHK-eGFP, and reduced plaque formation numbers by over 11-to 24-fold (Fig. 2C ). In addition, post infection with type Asia 1 FMDV Asia 1/JS/2005, the plaque formation number was reduced to over 13fold in BHK-sIFITM3 cells (Fig. 2C) .

title:
  Swine interferon-induced transmembrane protein, sIFITM3, inhibits foot-and-mouth disease virus infection in vitro and in vivo

abstract:
  The interferon-induced transmembrane protein 3 (IFITM3) is a widely expressed potent antiviral effector of the host innate immune system. It restricts a diverse group of pathogenic, enveloped viruses, by interfering with endosomal fusion. In this report, the swine IFITM3 (sIFITM3) gene was cloned. It shares the functionally conserved CD225 domain and multiple critical amino acid residues (Y19, F74, F77, R86 and Y98) with its human ortholog, which are essential for antiviral activity. Ectopic expression of sIFITM3 significantly inhibited non-enveloped foot-and-mouth disease virus (FMDV) infection in BHK-21 cells. Furthermore, sIFITM3 blocked FMDV infection at early steps in the virus life cycle by disrupting viral attachment to the host cell surface. Importantly, inoculation of 2-day-old suckling mice with a plasmid expressing sIFITM3 conferred protection against lethal challenge with FMDV. These results suggest that sIFITM3 is a promising antiviral agent and that can safeguard the host from infection with FMDV.


id: cord-295470-mua0qvst
author: Cui, Zhanding
date: 2020-06-21
txt: ./txt/cord-295470-mua0qvst.txt
cache: ./cache/cord-295470-mua0qvst.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354220302412
doi: 10.1016/j.antiviral.2020.104827
summary:
  In this study, we showed that both nitazoxanide and mizoribine had antiviral activity in F81 cells infected with different strains of FCV and also demonstrated a synergistic effect between the two drugs. (C and D) Virus TCID 50 values were calculated to determine the combined effect of different concentrations of NTZ (0-2.5 μM) and MZR (0-20 μM) on FCV. NTZ and MZR not only had antiviral efficacy against the FCV CH-JL2 strain, but the TCID 50 values of the CH-JL1, CH-JL3, CH-JL4 and CH-SH strains were also significantly different after drug treatment (p < 0.0332) (Figure 2A ). After oral NTZ treatment, either on -1 dpi or 3 dpi, levels of FCV in the trachea and lungs were significantly lower than in the control group (p < 0.0002) ( Figure 4F ). NTZ was shown to reduce viral load in the trachea and lungs and still had a therapeutic effect on FCV-infected cats when administered at 3 dpi.

title:
  Nitazoxanide Protects Cats from Feline Calicivirus Infection and Acts Synergistically with Mizoribine in vitro

abstract:
  Feline calicivirus (FCV) is a highly contagious pathogen that causes acute upper respiratory infections and oral disease in cats, thus seriously endangering feline health. Recently, there have been outbreaks of particularly virulent variant strains of FCV, which can cause both acute symptoms and fatal systemic disease. The discovery of effective antiviral agents to treat FCV infection is, therefore, gradually assuming increased importance. In this study, we showed that both nitazoxanide and mizoribine had antiviral activity in F81 cells infected with different strains of FCV and also demonstrated a synergistic effect between the two drugs. Experiments in cats challenged with FCV showed that nitazoxanide significantly reduced the clinical symptoms of FCV infection, reduced viral load in the trachea and lungs, and reduced viral shedding. Our results showed that nitazoxanide and mizoribine could potentially be used as therapeutic agents to treat FCV infection.


id: cord-297072-f5lmstyn
author: Struck, Anna-Winona
date: 2012-01-16
txt: ./txt/cord-297072-f5lmstyn.txt
cache: ./cache/cord-297072-f5lmstyn.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354211005481
doi: 10.1016/j.antiviral.2011.12.012
summary:
  title: A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2 Peptide (438)YKYRYL(443) is part of the receptor-binding domain (RBD) of the spike protein of SARS-CoV. The interaction of SARS-CoV with its receptor ACE2 is an attractive drug target as epitopes of the RBD on the spike protein may serve as leads for the design of effective entry inhibitors (Du et al., 2009) . This method allows the determination of the binding specificity, as Table 2 Synthetic peptide library of fourteen 6mer peptides comprising RBD-residues N435-E452 and A471-S500 of SARS-CoV spike protein. We found a hexapeptide in the receptor-binding domain (RBD) of the S protein of SARS-CoV that carries a significant portion of the binding affinity of the virus to the human cell. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein

title:
  A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2

abstract:
  In vitro infection of Vero E6 cells by SARS coronavirus (SARS-CoV) is blocked by hexapeptide Tyr-Lys-Tyr-Arg-Tyr-Leu. The peptide also inhibits proliferation of coronavirus NL63. On human cells both viruses utilize angiotensin-converting enzyme 2 (ACE2) as entry receptor. Blocking the viral entry is specific as alpha virus Sindbis shows no reduction in infectivity. Peptide (438)YKYRYL(443) is part of the receptor-binding domain (RBD) of the spike protein of SARS-CoV. Peptide libraries were screened by surface plasmon resonance (SPR) to identify RBD binding epitopes. (438)YKYRYL(443) carries the dominant binding epitope and binds to ACE2 with K(D) = 46 μM. The binding mode was further characterized by saturation transfer difference (STD) NMR spectroscopy and molecular dynamic simulations. Based on this information the peptide can be used as lead structure to design potential entry inhibitors against SARS-CoV and related viruses.


id: cord-297398-40bshqly
author: Dong, Wanyu
date: 2019-11-18
txt: ./txt/cord-297398-40bshqly.txt
cache: ./cache/cord-297398-40bshqly.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2019.104651
doi: 10.1016/j.antiviral.2019.104651
summary:
  To compare antiviral potencies, PK-15 cells were infected with TGEV at an MOI of 0.1 and then treated with DMSO or compounds at various concentrations, and the virus yield in the supernatants was determined at 36 hpi ( Fig. 1C and E). To explore whether the antiviral activity of A9 is affected by the cell type or virus-to-cell ratio, viral inhibition assays were performed in epithelial and fibroblast derived cell types and at various MOIs. Both PK-15 and ST cells were treated with A9 or vehicle control (DMSO) and infected with TGEV at an MOI of 0.01, 0.1, or 1. To explore whether A9 affects TGEV replication by inhibiting downstream mediators of the p38 or JNK MAPK pathways, we treated TGEV-infected PK-15 cells with the specific inhibitor BIRB796 or DB07268 and determined the toxicity of inhibitors in PK-15 cells using the MTT assay.

title:
  Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

abstract:
  Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV). We further performed a comparative phosphoproteomic analysis to investigate the mechanism of action of A9 against TGEV infection in vitro. We specifically identified p38 and JNK1, which are the downstream molecules of receptor tyrosine kinases (RTKs) required for efficient TGEV replication, as A9 targets through plaque assays, qRT-PCR and Western blotting assays. p38 and JNK1 inhibitors and RNA interference further showed that the inhibitory activity of A9 against TGEV infection was mainly mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. All these findings indicated that the RTKI A9 directly inhibits TGEV replication and that its inhibitory activity against TGEV replication mainly occurs by targeting p38, which provides vital clues to the design of novel drugs against CoVs.


id: cord-297531-et1sli23
title: A novel glycoprotein D-specific monoclonal antibody neutralizes herpes simplex virus
author: Du, Ruikun
date: 2017-10-20
txt: ./txt/cord-297531-et1sli23.txt
cache: ./cache/cord-297531-et1sli23.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354217304710
doi: 10.1016/j.antiviral.2017.10.013
summary:
  Our current investigation found a mAb, m27f that recognizes a new continuous epitope (residues 292 to 297) within the pro-fusion domain of HSV and possesses a high level of virus-neutralizing activity. Briefly, virusantibody mixture was incubated for 1 h at 4°C before inoculating over the Vero cells (pre-attachment), while prechilled (4°C for 15 min) Vero cells were infected with HSV-1 or HSV-2 (100 pfu/well) at 4°C for 1 h to allow virus adsorption before serial dilutions of antibodies were added (post-attachment). After 2 h of adsorption at 37°C, the virus inoculum was removed and cells were washed with PBS twice then incubated in DMEM containing 2% FBS in the presence of antibodies, m27f (500 μg/ml) and 21C11 (500 μg/ml), mouse IgG (500 μg/ml), or medium alone as a control. As shown in Fig. 4A , m27f completely inhibited cell-to-cell spread of both HSV-1 and HSV-2, as evidenced by observing the limited fluorescence caused by virus infection.

abstract:
  The worldwide prevalence of herpes simplex virus (HSV) and the shortage of efficient vaccines and novel therapeutic strategies against HSV are widely global concerns. The abundance on the virion and the major stimulus for the virus-neutralizing antibodies makes gD a predominant candidate for cure of HSV infection. In this study, we generated a monoclonal antibody (mAb), termed m27f, targeting to glycoprotein D (gD) of HSV-2, which also has cross-reactivity against HSV-1 gD. It has a high level of neutralizing activity against both HSV-1 and HSV-2, and binds to a highly conserved region (residues 292–297) within the pro-fusion domain of gD. It can effectively block HSV cell-to-cell spread in vitro. The pre- or post-attachment neutralization assay and syncytium formation inhibition assay revealed that m27f neutralizes HSV at the post-binding stage. Moreover, therapeutic administration of m27f completely prevented infection-related mortality of mice challenged with a lethal dose of HSV-2. Our newly identified epitope for the neutralizing antibody would facilitate studies of gD-based HSV entry or vaccine design, and m27f itself demonstrated a high potential for adaptation as a protective or therapeutic drug against HSV.


id: cord-298166-045evk7g
title: The molecular tweezer CLR01 inhibits Ebola and Zika virus infection
author: Röcker, Annika E.
date: 2018-02-08
txt: ./txt/cord-298166-045evk7g.txt
cache: ./cache/cord-298166-045evk7g.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354217308458
doi: 10.1016/j.antiviral.2018.02.003
summary:
  As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Methods describing the effect of CLR01 on pseudotyped lentiviral particles (2.3.), Ebola virus infection (2.4.), the detection of ZIKV infection by a colorimetric MTT assay (2.5.) or by cell-based ZIKV immunodetection assay (2.6.), flow cytometry (2.7.) and confocal microscopy (2.8.) as well as the RNA release assay (2.9.) and the antiviral activity of CLR01 in body fluids (2.10) can be found in the supplement.

abstract:
  Ebola (EBOV) and Zika viruses (ZIKV) are responsible for recent global health threats. As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. This small molecule has previously been shown to inactivate HIV-1 and herpes viruses through a selective interaction with lipid-raft-rich regions in the viral envelope, which results in membrane disruption and loss of infectivity. We found that CLR01 indeed blocked infection of EBOV and ZIKV in a dose-dependent manner. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Our findings show that CLR01 is a broad-spectrum inhibitor of enveloped viruses with prospects as a preventative microbicide or antiviral agent.


id: cord-298938-xemarhlv
author: Goswami, Biswendu B.
date: 2004-04-07
txt: ./txt/cord-298938-xemarhlv.txt
cache: ./cache/cord-298938-xemarhlv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15451183/
doi: 10.1016/j.antiviral.2004.02.004
summary:
  title: Apoptosis induced by a cytopathic hepatitis A virus is dependent on caspase activation following ribosomal RNA degradation but occurs in the absence of 2′–5′ oligoadenylate synthetase We have presented previously evidence that the cytopathogenic 18f strain of hepatitis A virus (HAV) induced degradation of ribosomal RNA (rRNA) in infected cells [Arch. Based on the pattern of rRNA degradation in intact ribosomes, we suggested that the 18f virus activates the interferon (IFN) controlled 2 -5 oligoadenylic acid-dependent RNase L pathway (for recent reviews, see Stark et al., 1998; Barber, 2001; Sen, 2001) . First, the level of IFN, 2 -5 OAS and RNase L mRNAs were investigated by RT-PCR to determine if any of these RNAs were induced following virus infection (Fig. 8) . RT-PCR amplification of selected cellular and viral mRNAs. Two microgram of RNA isolated from virus infected, IFN-␤, or dsRNA treated cells were reverse transcribed in a volume of 20 l using oligo(dT) 15 as primer as described in Section 2.

title:
  Apoptosis induced by a cytopathic hepatitis A virus is dependent on caspase activation following ribosomal RNA degradation but occurs in the absence of 2′–5′ oligoadenylate synthetase

abstract:
  We have presented previously evidence that the cytopathogenic 18f strain of hepatitis A virus (HAV) induced degradation of ribosomal RNA (rRNA) in infected cells [Arch. Virol. 148 (2003) 1275–1300]. In contrast, the non-cytopathogenic parent virus HM175 clone 1 had no effect on rRNA integrity. We present here data showing that rRNA degradation is followed by apoptosis accompanied by characteristic DNA laddering in the cytoplasm of 18f infected cells. The DNA laddering coincided with the detection of caspase 3 and PARP-1 cleavage and was dependent upon activation of the caspase pathway, since treatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited both events. RNase L mRNA was present in both virus-infected and uninfected cells. Messenger RNA for the interferon inducible enzyme 2′–5′ oligoadenylate synthetase (2′–5′ OAS), which polymerizes ATP into 2′–5′ oligo adenylate (2–5A, the activator of RNase L) in the presence of double-stranded RNA, was not detected following virus infection. 2′–5′ OAS mRNA was induced by treatment of the cells with interferon-β (IFN-β). IFN-β mRNA was marginally induced following infection. However, phosphorylated STAT 1, a key regulator of interferon-stimulated gene transcription was not detected in virus infected cells. STAT 1 phosphorylation in response to IFN treatment was lower in virus-infected cells, compared to uninfected cells treated with interferon, suggesting that 18f virus infection interferes with interferon signaling. The results suggest that 18f infection causes the induction of a 2–5A independent RNase L like activity.


id: cord-299189-59d4aojh
author: Zou, Hao
date: 2013-07-02
txt: ./txt/cord-299189-59d4aojh.txt
cache: ./cache/cord-299189-59d4aojh.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354213001721
doi: 10.1016/j.antiviral.2013.06.015
summary:
  title: Transmissible gastroenteritis virus: Identification of M protein-binding peptide ligands with antiviral and diagnostic potential In this study, the M protein of transmissible gastroenteritis virus (TGEV) was used to biopan a 12-mer phage display random peptide library. Plaque-reduction assays revealed that pepTGEV-M7 was able to prevent TGEV infection in vitro (p < 0.01) following pretreatment of the virus with the peptide. coli (Fig. 1) for use in biopanning the phage display library to identify peptides that bind the M protein of TGEV. Ten different TGEV-M protein-reactive phages were identified by ELISA, when rTGEV-M was used as the coating antigen (Fig. 2a) . 100TCID50 TGEV virus was pre-incubated with 2-fold, serially-diluted (500-31.25 lg/ml) peptide (pepTGEV-M7) then added to ST cells for 48 h. Bacterial expression of antigenic sites A and D in the spike protein of transmissible gastroenteritis virus and evaluation of their inhibitory effects on viral infection

title:
  Transmissible gastroenteritis virus: Identification of M protein-binding peptide ligands with antiviral and diagnostic potential

abstract:
  The membrane (M) protein is one of the major structural proteins of coronavirus particles. In this study, the M protein of transmissible gastroenteritis virus (TGEV) was used to biopan a 12-mer phage display random peptide library. Three phages expressing TGEV-M-binding peptides were identified and characterized in more depth. A phage-based immunosorbent assay (phage-ELISA) capable of differentiating TGEV from other coronaviruses was developed using one phage, phTGEV-M7, as antigen. When the phage-ELISA was compared to conventional antibody-based ELISA for detecting infections, phage-ELISA exhibited greater sensitivity. A chemically synthesized, TGEV-M7 peptide (pepTGEV-M7; HALTPIKYIPPG) was evaluated for antiviral activity. Plaque-reduction assays revealed that pepTGEV-M7 was able to prevent TGEV infection in vitro (p < 0.01) following pretreatment of the virus with the peptide. Indirect immunofluorescence and real-time RT-PCR confirmed the inhibitory effects of the peptide. These results indicate that pepTGEV-M7 might be utilized for virus-specific diagnostics and treatment.


id: cord-299224-7jgmxtzd
author: Zhu, Qingyuan
date: 2020-09-17
txt: ./txt/cord-299224-7jgmxtzd.txt
cache: ./cache/cord-299224-7jgmxtzd.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220303478?v=s5
doi: 10.1016/j.antiviral.2020.104933
summary:
  In this study, using dimeric amidobenzimidazole (diABZI), a newly discovered synthetic small molecule STING receptor agonist with much higher potency than CDNs, we found that activation of STING elicits potent antiviral effects against parainfluenza virus type 3 (PIV3) and human rhinovirus 16 (HRV16), two representative respiratory viral pathogens. In both PIV3-infected Hep2 and H1-HeLa cells, BX795 completely abolished the anti-PIV3 activity of diABZI, whereas no significant impairment was observed with CQ treatment, J o u r n a l P r e -p r o o f suggesting that the activation of immune responses via TBK1 plays a dominant role in STING-mediated anti-PIV3 activity (Figs. In this study, the diABZI STING agonist demonstrated potent antiviral activity against multiple respiratory RNA viruses, represented by PIV3 and HRV16, which broadly affect human health and have no effective treatment or vaccine.

title:
  A synthetic STING agonist inhibits the replication of Human Parainfluenza Virus 3 and Rhinovirus 16 through distinct mechanisms

abstract:
  Stimulator of interferon genes (STING), as a signaling hub in innate immunity, plays a central role for the effective initiation of host defense mechanisms against microbial infections. Upon binding of its ligand cyclic dinucleotides (CDNs) produced by the cyclic GMP-AMP synthase (cGAS) or invading bacteria, STING is activated, leading to the induction of both type I interferon responses and autophagy, which are critical for the control of certain microbial infections. RNA viruses, such as Parainfluenza virus (PIV) and Rhinovirus (HRV), are among the leading causes of respiratory infections that affect human health without effective treatments. Activation of STING pathway may provide a new therapeutic approach fighting against these viruses. However, the role of STING in the control of RNA virus infection remains largely unexplored. In this study, using dimeric amidobenzimidazole (diABZI), a newly discovered synthetic small molecule STING receptor agonist with much higher potency than CDNs, we found that activation of STING elicits potent antiviral effects against parainfluenza virus type 3 (PIV3) and human rhinovirus 16 (HRV16), two representative respiratory viral pathogens. Notably, while anti-PIV3 activity was depend on the induction of type I interferon responses through TANK-binding kinase 1 (TBK1), anti-HRV16 activity required the induction of autophagy-related gene 5 (ATG5)-dependent autophagy, indicating that two distinct antiviral mechanisms are engaged upon STING activation. Antiviral activity and individual specific pathway was further confirmed in infected primary bronchial epithelial cells. Our findings thus demonstrate the distinct antiviral mechanisms triggered by STING agonist and uncover the potential of therapeutic effect against different viruses.


id: cord-299964-sn5o3ugb
author: Xue, Qiao
date: 2018-11-05
txt: ./txt/cord-299964-sn5o3ugb.txt
cache: ./cache/cord-299964-sn5o3ugb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30408499/
doi: 10.1016/j.antiviral.2018.10.028
summary:
  Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. To determine whether SVV can evade innate immune response by inhibiting the host ubiquitination, HEK293T cells were transfected with FLAG-tagged VP1, VP2, 2AB, 2B, 2C, 3D, 3C plasmids along with HA-Ub plasmid. As shown in Fig. 1A , expression of 3C pro resulted in a dose-dependent reduction of the level of ubiquitinated cellular proteins compared with that in the empty vector-transfected cells. Taken together, these results indicate that SVV and 3C pro inhibit the ubiquitination of RIG-I, TBK1, and TRAF3 in a DUB-dependent manner.

title:
  Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

abstract:
  The mechanisms that enable Seneca Valley Virus (SVV) to escape the host innate immune response are not well known. Previous studies demonstrated that SVV 3C(pro) suppresses innate immune responses by cleavage of host proteins and degradation of IRF3 and IRF7 protein expression. Here, we showed that SVV 3C protease (3C(pro)) has deubiquitinating activity. Overexpressed 3C(pro) inhibits the ubiquitination of cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. SVV infection also possessed deubiquitinating activity. The ubiquitin-proteasome system was significantly involved in SVV replication. Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. Together, our results demonstrate a novel mechanism developed by SVV 3C(pro) to promote viral replication, and may also provide a novel strategy for improving ubiquitination-based therapy.


id: cord-300117-rlpzejjt
author: Coutard, B.
date: 2020-02-10
txt: ./txt/cord-300117-rlpzejjt.txt
cache: ./cache/cord-300117-rlpzejjt.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354220300528
doi: 10.1016/j.antiviral.2020.104742
summary:
  In the case of human-infecting coronaviruses such as HCoV-OC43 (Le Coupanec et al., 2015) , MERS-CoV (Millet and Whittaker, 2014) , and HKU1 (Chan et al., 2008) the spike protein has been demonstrated to be cleaved at an S1/S2 cleavage site (Fig. 2) generating the S1 and S2 subunits. The furin-like S2′ cleavage site at KR↓SF with P1 and P2 basic residues and a P2′ hydrophobic Phe (Seidah and Prat, 2012) , downstream of the IFP is identical between the 2019-nCoV and SARS-CoV (Fig. 2) . However, in the other less pathogenic circulating human CoV, the S2′ cleavage site only exhibits a monobasic R↓S sequence (Fig. 2) with no basic residues at either P2 and/or P4 needed to allow furin cleavage, suggesting a less efficient cleavage or higher restriction at the entry step depending on the cognate proteases expressed by target cells.

title:
  The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

abstract:
  In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.


id: cord-308110-cco3aq4n
title: The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro
author: Okamoto, Mika
date: 2020-07-30
txt: ./txt/cord-308110-cco3aq4n.txt
cache: ./cache/cord-308110-cco3aq4n.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2020.104902
doi: 10.1016/j.antiviral.2020.104902
summary:
  In this study, CVC was examined for its inhibitory effect on the replication of SARS-CoV-2, the causative agent of COVID-19, in cell cultures and found to be a selective inhibitor of the virus. The 50% effective concentrations of CVC were 19.0 and 2.9 μM in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively. Considering the fact that the regulation of excessive immune activation is required to treat COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection. Since not only the inhibition of viral replication but also the control of excessive immune activation is mandatory to save COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection.

abstract:
  Cenicriviroc (CVC) is a small-molecule chemokine receptor antagonist with highly potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity through antagonizing C-C chemokine receptor type 5 (CCR5) as a coreceptor of HIV-1. CVC also strongly antagonizes C-C chemokine receptor type 2b (CCR2b), thereby it has potent anti-inflammatory and immunomodulatory effects. CVC is currently under clinical trials in the patients for treatment of nonalcoholic steatohepatitis, in which immune cell activation and dysregulation of proinflammatory cytokines play an important role in its pathogenesis. In this study, CVC was examined for its inhibitory effect on the replication of SARS-CoV-2, the causative agent of COVID-19, in cell cultures and found to be a selective inhibitor of the virus. The 50% effective concentrations of CVC were 19.0 and 2.9 μM in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively. Interestingly, the CCR5-specific antagonist maraviroc did not show any anti-SARS-CoV-2 activity. Although the mechanism of SARS-CoV-2 inhibition by CVC remains to be elucidated, CCR2b does not seem to be its target molecule. Considering the fact that the regulation of excessive immune activation is required to treat COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection.


id: cord-310469-v4p01rze
title: In vitro and in vivo studies of the Interferon-alpha action on distinct Orthobunyavirus
author: Livonesi, Márcia Cristina
date: 2007-02-28
txt: ./txt/cord-310469-v4p01rze.txt
cache: ./cache/cord-310469-v4p01rze.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/17368573/
doi: 10.1016/j.antiviral.2007.01.158
summary:
  Thus, in an effort to characterize antiviral agents that could attenuate infections caused by OROV, CARV, GMAV, GROV and TCMV, we tested the in vitro and in vivo actions of IFN-␣ on these viruses. However, treatment of CARV-, GMAV-or TCMV-infected mice with IFN-␣A did not result in an increase in survival or prolongation of the mean time to death and did not prevent virus replication in the brain of animals (Table 2 and Fig. 3, respectively) . Treatment with IFN-␣A initiated 24 h after mice infection by GROV was unable to inhibit either the death of animals or the viral replication in the brain (Table 3 and Fig. 5 , respectively). In vitro and in vivo results showed that IFN-␣ was able to prevent viral replication in a limited manner, exerting antiviral effect only when administrated early and in high doses, suggesting that OROV, CARV, GMAV, GROV and TCMV present some escape mechanism from antiviral actions of the IFN-␣.

abstract:
  Oropouche, Caraparu, Guama, Guaroa and Tacaiuma viruses (Orthobunyavirus genus) cause human febrile illnesses and/or encephalitis. To achieve a therapeutical agent to prevent and/or treat these diseases we evaluated the antiviral action of Interferon-alpha (IFN-α) on these orthobunyaviruses. In vitro results showed that all the studied orthobunyaviruses are susceptible to antiviral action of IFN-α, but this susceptibility is limited and dependent on both concentration of drug and treatment period. In vivo results demonstrated that IFN-α present antiviral action on Oropouche and Guaroa viruses when used as a prophylactic treatment. Moreover, a treatment initiated 3 h after infection prevented the death of Guaroa virus infected-mice. Additionally, mortality of mice was related to the migration and replication of viruses in their brains. Our results suggest that IFN-α could be potentially useful in the prevention of diseases caused by Oropouche virus and in the prevention and/or treatment of diseases caused by Guaroa virus.


id: cord-312688-12san3m7
author: Martin, Baptiste
date: 2016-09-14
txt: ./txt/cord-312688-12san3m7.txt
cache: ./cache/cord-312688-12san3m7.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354216304077
doi: 10.1016/j.antiviral.2016.09.001
summary:
  title: Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry After replication of the viral genome and RNA transcription, nascent viral particles are assembled in a process mediated by the matrix protein VP40, and virus budding occurs at the cell surface membrane in a process that involves hijacking the host ESCRT machinery (Hartlieb and Weissenhorn, 2006; Noda et al., 2006) . However, no direct interaction between both molecules has been demonstrated yet, and recent studies suggest that a 5 b 1 -integrin is not required for GP-mediated binding of internalization, but rather is a positive regulator of cathepsins, which play an important role in processing GP 1 into its fusion-competent form within the endosomes of infected cells (Schornberg et al., 2009) . After attachment mediated by interaction between the filovirus surface protein GP 1,2 (PDB: 3CSY) and various attachment factors, the complex is internalized and routed to the endosome, where GP 1,2 is processed to trigger fusion of viral and host membranes.

title:
  Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry

abstract:
  This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the surface glycoprotein GP(1,2) and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and Δ-peptide. Then, we compare filovirus surface GP(1,2) proteins in terms of structure, synthesis and function. As they bear potential in drug-design, the discovery of small organic compounds inhibiting filovirus entry is a currently very active field. Although it is at an early stage, the development of antiviral drugs against Ebola and Marburg virus entry might prove essential to reduce outbreak-associated fatality rates through post-exposure treatment of both suspected and confirmed cases.


id: cord-312965-5hcb15xc
title: In vitro anti-hepatitis B and SARS virus activities of a titanium-substituted-heteropolytungstate
author: Qi, Yan-fei
date: 2011-11-23
txt: ./txt/cord-312965-5hcb15xc.txt
cache: ./cache/cord-312965-5hcb15xc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22127069/
doi: 10.1016/j.antiviral.2011.11.003
summary:
  A structural determined heteropolytungstate, [K(4)(H(2)O)(8)Cl][K(4)(H(2)O)(4)PTi(2)W(10)O(40)]·NH(2)OH 1, has been synthesized and evaluated for in vitro antiviral activities against hepatitis B (HBV) and SARS virus. The levels of HBsAg, HBeAg and extracellular HBV DNA in the medium were measured at different time points in the control group, ADV group, and compound 1 group, respectively, as shown in Fig. 4 . The levels of HBeAg, HBsAg and extracellular HBV DNA decreased with time in HepG 2.2.15 cells, indicating that the anti-HBV activity of compound 1 is time-dependent (P < 0.01). To characterize the anti-HBV mechanism of compound 1, the amounts of intracellular viral pgRNA and DNA were measured in the control group, ADV group, and compound 1 group at different concentrations, respectively, at day 5, as shown in Fig. 5 . to the cytotoxic results, compound 1 was diluted at five non-toxic concentrations (31.2, 15.6, 7.8, 3.9 , and 1.95 lM) and the anti-SARS virus activity was checked with MTT assay.

abstract:
  A structural determined heteropolytungstate, [K(4)(H(2)O)(8)Cl][K(4)(H(2)O)(4)PTi(2)W(10)O(40)]·NH(2)OH 1, has been synthesized and evaluated for in vitro antiviral activities against hepatitis B (HBV) and SARS virus. The identity and high purity of compound 1 were confirmed by elemental analysis, NMR, IR analysis and single-crystal X-ray diffraction. The compound 1, evaluated in HepG 2.2.15 cells expressing permanently HBV, significantly reduced the levels of HBV antigens and HBV DNA in a dose-dependent and time-dependent manner. EC(50) values were determined to be 54 μM for HBeAg, 61 μM for HBsAg and 2.66 μM for supernatant HBV DNA, as compared to 1671, 1570, 169 μM, respectively, for the commercially-available hepatitis B drug adefovir dipivoxil (ADV). Intracellular cccDNA, pgRNA and HBcAg were also found to be decreased by compound 1 in a concentration-dependent manner. Cytotoxicity results showed that compound 1 has low toxicity in HepG 2 cells with CC(50) value of 515.20 μM. The results indicate that compound 1 can efficiently inhibit HBV replication in HepG 2.2.15 cells line in vitro. Additionally, compound 1 also shows high anti-SARS activity at an EC(50) of 7.08 μM and toxicity with a CC(50) of 118.6 μM against MDCK cells.


id: cord-314833-6fue84x6
title: The SARS coronavirus nucleocapsid protein – Forms and functions
author: Chang, Chung-ke
date: 2014-01-11
url: https://www.ncbi.nlm.nih.gov/pubmed/24418573/
doi: 10.1016/j.antiviral.2013.12.009
abstract:
  The nucleocapsid phosphoprotein of the severe acute respiratory syndrome coronavirus (SARS-CoV N protein) packages the viral genome into a helical ribonucleocapsid (RNP) and plays a fundamental role during viral self-assembly. It is a protein with multifarious activities. In this article we will review our current understanding of the N protein structure and its interaction with nucleic acid. Highlights of the progresses include uncovering the modular organization, determining the structures of the structural domains, realizing the roles of protein disorder in protein–protein and protein–nucleic acid interactions, and visualizing the ribonucleoprotein (RNP) structure inside the virions. It was also demonstrated that N-protein binds to nucleic acid at multiple sites with a coupled-allostery manner. We propose a SARS-CoV RNP model that conforms to existing data and bears resemblance to the existing RNP structures of RNA viruses. The model highlights the critical role of modular organization and intrinsic disorder of the N protein in the formation and functions of the dynamic RNP capsid in RNA viruses. This paper forms part of a symposium in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”


id: cord-315524-vgdjpjkj
author: Chen, Sunrui
date: 2020-05-30
txt: ./txt/cord-315524-vgdjpjkj.txt
cache: ./cache/cord-315524-vgdjpjkj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32485209/
doi: 10.1016/j.antiviral.2020.104823
summary:
  We identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of rotavirus infection. Supplementation of UTP or uridine largely abolished the anti-rotavirus activity of gemcitabine, suggesting its function through inhibition of pyrimidine biosynthesis pathway. Furthermore, immunofluorescent staining of viral capsid protein (VP6) showed significant reduction of the number of infected Caco2 cells by gemcitabine treatment (Fig. 1F, 1G, Supplementary Fig. S2 ). Our previous studies have evaluated the effects of the nucleoside analog ribavirin and mycophenolic acid (MPA), and the antiviral cytokine interferon alpha (IFN-α) on rotavirus in cell culture models. We have previously established modeling of rotavirus infection in intestinal organoids, which allows the study of virus-host interactions and assessment of antiviral drugs (Yin et al., 2015a; Yin et al., 2018a; Yin et al., 2018b; Yin et al., 2016) . Gemcitabine, a widely used anti-cancer drug, has potent antiviral activity against rotavirus infection Gemcitabine exerts its anti-rotavirus effect through inhibiting pyrimidine biosynthesis pathway

title:
  Drug screening identifies gemcitabine inhibiting rotavirus through alteration of pyrimidine nucleotide synthesis pathway

abstract:
  Although rotavirus infection is usually acute and self-limiting, it can cause chronic infection with severe diseases in immunocompromised patients, including organ transplantation recipients and cancer patients irrespective of pediatric or adult patients. Since no approved medication against rotavirus infection is available, this study screened a library of safe-in-man broad-spectrum antivirals. We identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of rotavirus infection. We confirmed this effect in 2D cell cultures and 3D cultured human intestinal organoids with both laboratory-adapted rotavirus strains and five clinical isolates. Supplementation of UTP or uridine largely abolished the anti-rotavirus activity of gemcitabine, suggesting its function through inhibition of pyrimidine biosynthesis pathway. Our results support repositioning of gemcitabine for treating rotavirus infection, especially for infected cancer patients.


id: cord-316503-wtmmewiz
title: Advanced morpholino oligomers: A novel approach to antiviral therapy
author: Warren, Travis K.
date: 2012-02-14
txt: ./txt/cord-316503-wtmmewiz.txt
cache: ./cache/cord-316503-wtmmewiz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22353544/
doi: 10.1016/j.antiviral.2012.02.004
summary:
  Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense oligonucleotide analogs that are designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Peptide conjugated PMOs (PPMOs; Fig. 2 ), which include positively charged amino acid residues such as arginine, have been viewed as particularly promising transporters and have shown efficacy in multiple in vivo models of viral infection (Enterlein et al., 2006; Paessler et al., 2008; Stein, 2008; Swenson et al., 2009) . While PPMOs are efficacious in multiple in vivo models of viral infections, PPMOs are more poorly tolerated in vivo compared to neutral-charge PMOs. In mice, dose-dependent reductions in weight, behavioral alterations, and mild liver histopathology were observed following repeat administration of 200-300 lg doses of a PMO conjugated to an arginine-rich peptide (Deas et al., 2007) .

abstract:
  Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense oligonucleotide analogs that are designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Positively charged PMOs (PMOplus™) are effective for the postexposure protection of two fulminant viral diseases, Ebola and Marburg hemorrhagic fever in nonhuman primates, and this class of antisense agent may also have possibilities for treatment of other viral diseases. PMOs are highly stable, are effective by a variety of routes of administration, can be readily formulated in common isotonic delivery vehicles, and can be rapidly designed and synthesized. These are properties which may make PMOs good candidates for use during responses to emerging or reemerging viruses that may be insensitive to available therapies or for use during outbreaks, especially in regions that lack a modern medical infrastructure. While the efficacy of sequence-specific therapies can be limited by target-site sequence variations that occur between variants or by the emergence of resistant mutants during infections, various PMO design strategies can minimize these impacts. These strategies include the use of promiscuous bases such as inosine to compensate for predicted base-pair mismatches, the use of sequences that target conserved sites between viral strains, and the use of sequences that target host products that viruses utilize for infection.


id: cord-316624-bqaqhp3m
author: Sui, Xiuwen
date: 2009-10-30
txt: ./txt/cord-316624-bqaqhp3m.txt
cache: ./cache/cord-316624-bqaqhp3m.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354209005014
doi: 10.1016/j.antiviral.2009.10.014
summary:
  Virus plaque-reduction assays, PCR and RT-PCR analysis indicated that both drugs inhibited cell infection by PrV. Briefly, FITC-conjugated Annexin V (50 l/well) and propidium iodide, PI (50 l/well) were added the cells infected by drug-treated viruses, or the virus-infected cells treated with LiCl in 24-well plates and incubated at room temperature for 15 min in the dark prior to fluorescence observation. At the maximum non-toxic concentration of the drugs, the inhibition rate of LiCl and DG for PrV infection in cell culture reached 100% (Fig. 4) . The effect of both drugs on PrV-infected cells was analyzed using plaque-reduction assays. As shown in Fig. 9 , the maximum nontoxic concentration of drugs had an inhibitory activity against PrV-induced cell apoptosis. It is possible that the observed anti-apoptotic effect of DG and LiCl during PRV infection is indirect and due to the reduced virus replication caused by the drugs.

title:
  Antiviral effect of diammonium glycyrrhizinate and lithium chloride on cell infection by pseudorabies herpesvirus

abstract:
  Diammonium glycyrrhizin (DG), a salt from glycyrrhizinate (GL) that is a major active component of licorice root extract with various pharmacological activities was investigated for its inhibitory effect on pseudorabies virus (PrV) infection. In parallel, lithium chloride (LiCl), a chemical reagent with potential antiviral activity was compared with DG for their inhibitory ability against PrV infection in vitro. Virus plaque-reduction assays, PCR and RT-PCR analysis indicated that both drugs inhibited cell infection by PrV. Moreover, addition of the drugs resulted in fewer apoptotic cells during PrV infection.


id: cord-316996-8yimrpaz
title: The use of sialidase therapy for respiratory viral infections
author: Nicholls, John M.
date: 2013-04-17
txt: ./txt/cord-316996-8yimrpaz.txt
cache: ./cache/cord-316996-8yimrpaz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2013.04.012
doi: 10.1016/j.antiviral.2013.04.012
summary:
  DAS181 is an inhaled bacterial sialidase which functions by removing sialic acid (Sia) from the surface of epithelial cells, preventing attachment and subsequent infection by respiratory viruses that utilize Sia as a receptor. DAS181 is the first antiviral compound in Phase II development that functions by blocking this pathogen-host interaction, by destroying the influenza host-cell receptor, sialic acid (Sia), on the surface of respiratory epithelial cells. In this paper, we provide background information on Sia and sialidases; discuss the potential role of bacterial sialidases as antiviral agents; review the in vitro and Phase II evaluation of DAS181 for the treatment of influenza; and note evidence that the drug would also be useful against parainfluenza virus infections. Even though influenza virus has been the most well characterized of the pathogens studied, it must be noted that other viruses, including cytomegalovirus (Taylor and Cooper, 1989) , rhinovirus 87 (Blomqvist et al., 2002) , mumps Urabe AM9 (ReyesLeyva et al., 2007) and the paramyxoviruses all utilize Sia (Suzuki et al., 2001) (Paulson et al., 1979) , suggesting that sialidase treatment may potentially be useful for these infections.

abstract:
  DAS181 is an inhaled bacterial sialidase which functions by removing sialic acid (Sia) from the surface of epithelial cells, preventing attachment and subsequent infection by respiratory viruses that utilize Sia as a receptor. DAS181 is typical of bacterial sialidases in cleaving Sia α2-3 and Sia α2-6 linkages, and it also has a demonstrated effect against acetylated and hydroxylated forms of Sia. The potency of the compound has been enhanced by coupling the active sialidase with an amphiregulin tag, allowing a longer duration of action and minimizing spread to the systemic circulation. DAS181 is now in Phase II development for the treatment of influenza, and it has also demonstrated activity in individual cases of parainfluenza in immunosuppressed patients. Continued evaluation of the roles and activities of bacterial sialidases is required to expand the range of successful antiviral therapies targeting Sia or its derivatives.


id: cord-328468-bwn4bmf5
title: Antiviral activity of selected antimicrobial peptides against vaccinia virus()
author: Mohan, Ketha V.K.
date: 2010-03-27
txt: ./txt/cord-328468-bwn4bmf5.txt
cache: ./cache/cord-328468-bwn4bmf5.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S016635421000553X
doi: 10.1016/j.antiviral.2010.03.012
summary:
  We have recently demonstrated the antibacterial activity of two types of AMPs, the thrombin-induced human platelet-derived antimicrobial peptides (PD) and the arginine-tryptophan (RW) repeat peptides, against aerobic bacterial contaminants encountered in blood products (Mohan et al., 2009a) . PD3, PD4 and RW3 peptides were each incubated with the virus inoculum for 2 h at room temperature and tested for antiviral activity by performing the plaque assay as described in the pre-infection experiment. Analysis of the post virus-binding experiment revealed that none of the PD or RW peptides were able to inhibit virus infection as there was no significant difference in the viral titers between the test and control groups (Fig. 2) . Human plasma samples spiked with 10 2 pfu of VV-WR virus were incubated with PD3, PD4 and RW3 peptides individually for 2 h and tested for antiviral activity by infecting B-SC-1 cells and measuring virus titer by performing the plaque assay as described in the pre-infection experiment.

abstract:
  Antimicrobial peptides (AMPs) are gaining importance as effective therapeutic alternatives to conventional antibiotics. Recently we have shown that a set of nine synthetic antimicrobial peptides, four originating from thrombin-induced human platelet-derived antimicrobial proteins named PD1–PD4 and five synthetic repeats of arginine-tryptophan (RW) repeats (RW1-5) demonstrate antibacterial activity in plasma and platelets. Using WR strain of vaccinia virus (VV) as a model virus for enveloped virus in the present study, we tested the same nine synthetic peptides for their antiviral activity. A cell culture-based standard plaque reduction assay was utilized to estimate antiviral effectiveness of the peptides. Our analysis revealed that peptides PD3, PD4, and RW3 were virucidal against VV with PD3 demonstrating the highest antiviral activity of 100-fold reduction in viral titers, whereas, PD4 and RW3 peptide treatments resulted in 10–30-fold reduction. The EC(50) values of PD3, PD4 and RW3 were found to be 40 μg/ml, 50 μg/ml and 6.5 μM, respectively. In VV-spiked plasma samples, the virucidal activity of PD3, PD4 and RW3 was close to 100% (90–100-fold reduction). Overall, the present study constitutes a new proof-of-concept in developing peptide therapeutics for vaccinia virus infections in biothreat scenarios and as in vitro viral reduction agents.


id: cord-329494-cdn52epy
title: Inhibition of Junín virus replication by small interfering RNAs
author: Artuso, María C.
date: 2009-07-08
txt: ./txt/cord-329494-cdn52epy.txt
cache: ./cache/cord-329494-cdn52epy.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2009.07.001
doi: 10.1016/j.antiviral.2009.07.001
summary:
  The efficacy of this Z2-siRNA against JUNV was also demonstrated in virus-infected cells, by testing infectious virus plaque formation (92.8% JUNV yield reduction), viral RNA level or antigen expression, as well as in cells transfected with Z-specific reporter plasmids (91% reduction in expression of Z-EGFP fusion protein). (E) Expression of viral antigens in Vero cells transfected with Z2-siRNA or X-siRNA and infected with JUNV was detected by immunofluorescence assay using a rabbit anti-JUNV polyclonal serum. The efficacy of this agent against JUNV was also demonstrated in virus-infected cells by testing infectious virus plaque formation, viral RNA or antigen expression, as well as in cells transfected with Z-specific reporter plasmids. The present study represents the first report of virus inhibition mediated by RNA interference for a New World arenavirus, a group in the family including four agents of severe viral hemorrhagic fevers in South America (JUNV, Machupo, Sabiá and Guanarito viruses).

abstract:
  Junín virus (JUNV), the etiological agent of the Argentine hemorrhagic fever, has a single-stranded RNA genome with ambisense expression which encodes for five proteins. In previous works we have demonstrated that the Z arenavirus matrix protein represents an attractive target for antiviral therapy. With the aim of studying a new alternative therapeutic mechanism, four Z-specific siRNAs (Z1- to Z4-siRNAs) were tested showing variable efficacy. The most effective inhibitor was Z2-siRNA targeted at the region encompassed by nt 179–197 of Z gene. The efficacy of this Z2-siRNA against JUNV was also demonstrated in virus-infected cells, by testing infectious virus plaque formation (92.8% JUNV yield reduction), viral RNA level or antigen expression, as well as in cells transfected with Z-specific reporter plasmids (91% reduction in expression of Z-EGFP fusion protein). Furthermore, the lack of effect of this Z-siRNA on the expression of other JUNV proteins, such as N and GPC, confirmed the specificity of action exerted by Z2-siRNA on Z transcript. Thus, the present study represents the first report of virus inhibition mediated by RNA interference for a New World arenavirus.


id: cord-329642-5t8yuq4v
title: Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo
author: Takano, Tomomi
date: 2013-05-03
txt: ./txt/cord-329642-5t8yuq4v.txt
cache: ./cache/cord-329642-5t8yuq4v.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/23648708/
doi: 10.1016/j.antiviral.2013.04.016
summary:
  Several agents that significantly inhibit FCoV replication in vitro have been identified (Balzarini et al., 2006; Barlough and Shacklett, 1994; Hsieh et al., 2010; Kim et al., 2012; Takano et al., 2008) ; however, whether or not these agents exhibit a therapeutic effect in cats with FIP has not been investigated. The effect of chloroquine on FIPV infection in fcwf-4 cells and SPF cat-derived monocytes was investigated. In monocytes inoculated with a mixture of FIPV and MAb 6-4-2, IL-1b, TNF-a and IL-6 mRNA expression levels were significantly lower in the Pre/Post treatment group than in the None group (Fig. 3B) . The influence of chloroquine on cytokine mRNA and FCoV N gene expressions was investigated in monocytes from cats with FIP. IL-1b, TNF-a, and IL-6 mRNA expression levels of PBMC in FIPV-infected cats treated with chloroquine. In this study, chloroquine significantly inhibited inflammatory cytokine mRNA expression levels in FIPV-infected monocytes.

abstract:
  Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents.


id: cord-329959-4yecwdlo
title: Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes
author: Lin, Min-Han
date: 2017-12-28
txt: ./txt/cord-329959-4yecwdlo.txt
cache: ./cache/cord-329959-4yecwdlo.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.antiviral.2017.12.015
doi: 10.1016/j.antiviral.2017.12.015
summary:
  Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PL(pro)s) of MERS-CoV and SARS-CoV. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL(pro) by disulfiram, while synergistic inhibition of MERS-CoV PL(pro) by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs. For the inactivation studies, SARS-CoV PL pro (0.05 μM in 20 mM phosphate buffer, pH 6.5) was incubated with different concentrations of disulfiram and peptide substrate, and enzymatic activity was traced for 5 min. On the other hand, the results of kinetic assays, continued inactivation after the removal of disulfiram, reactivation by reductant, and the phenomenon of slow-binding inhibition suggest that disulfiram may act at the active site of SARS-CoV PL pro , forming a covalent adduct with residue Cys112.

abstract:
  Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PL(pro)s) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL(pro) but as a competitive (or mixed) inhibitor of SARS-CoV PL(pro). The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL(pro) by disulfiram, while synergistic inhibition of MERS-CoV PL(pro) by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.


id: cord-332952-d5l60cgc
title: MERS: Progress on the global response, remaining challenges and the way forward
author: nan
date: 2018-09-17
txt: ./txt/cord-332952-d5l60cgc.txt
cache: ./cache/cord-332952-d5l60cgc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30236531/
doi: 10.1016/j.antiviral.2018.09.002
summary:
  Typical of an emerging zoonosis, Middle East respiratory syndrome coronavirus (MERS-CoV) has an animal reservoir, i.e. dromedary camels in which the virus causes little to no disease (Mohd et al., 2016) . For example, studies of respiratory pathogens (Yu et al., 2007; Tran et al., 2012; Thompson et al., 2013) and MERS-CoV conducted in the Middle East (Assiri et al., 2013; Oboho et al., 2015; Hunter et al., 2016; Balkhy et al., 2016) and the Republic of Korea (Bin et al., 2016; Kim et al., 2016a Kim et al., , 2016b Nam et al., 2017) illustrate that aerosol-generating procedures and non-invasive ventilation, combined with inappropriate infection prevention and control practices and lack of adherence to standard practices had an important role in facilitating human-to-human transmission in health care settings. The critical care response to a hospital outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: an observational study Sero-prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) specific antibodies in dromedary camels in Tabuk, Saudi Arabia

abstract:
  This article summarizes progress in research on Middle East Respiratory Syndrome (MERS) since a FAO-OIE-WHO Global Technical Meeting held at WHO Headquarters in Geneva on 25–27 September 2017. The meeting reviewed the latest scientific findings and identified and prioritized the global activities necessary to prevent, manage and control the disease. Critical needs for research and technical guidance identified during the meeting have been used to update the WHO R&D MERS-CoV Roadmap for diagnostics, therapeutics and vaccines and a broader public health research agenda. Since the 2017 meeting, progress has been made on several key actions in animal populations, at the animal/human interface and in human populations. This report also summarizes the latest scientific studies on MERS since 2017, including data from more than 50 research studies examining the presence of MERS-CoV infection in dromedary camels.


id: cord-336093-ic6q6ke8
author: Sun, Ying
date: 2014-02-11
txt: ./txt/cord-336093-ic6q6ke8.txt
cache: ./cache/cord-336093-ic6q6ke8.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354214000369
doi: 10.1016/j.antiviral.2014.02.002
summary:
  Abbreviations: SARS, severe acute respiratory syndrome; SARS-CoV, SARS coronavirus; nsp, nonstructural protein; N7-MTase, guanine-N7-methyltransferase; 2 0 -O-MTase, 2 0 -O-methyltransferase; AdoMet, S-adenosyl-L-methionine; AdoHcy, S-adenosyl-L-homocysteine; ATA, aurintricarboxylic acid; IC 50 , inhibitory concentration at 50% activity. A single transformed colony of the YBS40 strain containing plasmids expressing human N7-MTase (MT-Human), SARS-CoV N7-MTase (MT-SARS), N7-MTases of other coronaviruses (MT-MHV, MT-TGEV, and MT-IBV), and the pMceK294A vector as control (representing the yeast N7-MTase [MT-Yeast]), were inoculated separately into 5 ml of a basic medium (Min SD Base) lacking tryptophan and incubated at 30°C for 21-24 h until reaching a similar final cell density in the stationary phase (0.5-1.0 Â 10 8 cells/ml) (Chrebet et al., 2005) . Although AdoHcy, ATA and sinefungin, were previously reported to be inhibitors of coronavirus RNA MTases in vitro , only sinefungin significantly suppressed the growth of the MT-yeast, MT-human, and MT-SARS yeast cells (Fig. 3 ).

title:
  Yeast-based assays for the high-throughput screening of inhibitors of coronavirus RNA cap guanine-N7-methyltransferase

abstract:
  The 5′-cap structure is a distinct feature of eukaryotic mRNAs and is important for RNA stability and protein translation by providing a molecular signature for the distinction of self or non-self mRNA. Eukaryotic viruses generally modify the 5′-end of their RNAs to mimic the cellular mRNA structure, thereby facilitating viral replication in host cells. However, the molecular organization and biochemical mechanisms of the viral capping apparatus typically differ from its cellular counterpart, which makes viral capping enzymes attractive targets for drug discovery. Our previous work showed that SARS coronavirus (SARS-CoV) non-structural protein 14 represents a structurally novel and unique guanine-N7-methyltransferase (N7-MTase) that is able to functionally complement yeast cellular N7-MTase. In the present study, we developed a yeast-based system for identifying and screening inhibitors against coronavirus N7-MTase using both 96-well and 384-well microtiter plates. The MTase inhibitors previously identified by in vitro biochemical assays were tested, and some, such as sinefungin, effectively suppressed N7-MTase in the yeast system. However, other compounds, such as ATA and AdoHcy, did not exert an inhibitory effect within a cellular context. These results validated the yeast assay system for inhibitor screening yet also demonstrated the difference between cell-based and in vitro biochemical assays. The yeast system was applied to the screening of 3000 natural product extracts, and three were observed to more potently inhibit the activity of coronavirus than human N7-MTase.


id: cord-336517-v7z62tld
author: Chu, Hsu-Feng
date: 2018-08-20
txt: ./txt/cord-336517-v7z62tld.txt
cache: ./cache/cord-336517-v7z62tld.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0166354218302183
doi: 10.1016/j.antiviral.2018.08.011
summary:
  Further studies suggest that PEDV PL2 pro exhibits much higher DUB activity than that of SARS-and MERS-CoV PL pro s and can be inhibited by the anti-leukemia drug 6-thioguanine (6TG). Previous studies suggested that the Ubl domain was not involved in the catalytic activity of SARS-and MERS-CoV PL pro s (Chou et al., 2012; Clasman et al., 2017) . Overall, the secondary, tertiary and quaternary structures of the PEDV PL2 pro catalytic core are similar to those of SARS-and MERS-CoV PL pro s, even though their sequence identity is only 22-25% (Fig. S1 ). In contrast, previous studies suggested that the binding site of 6TG for SARS-and MERS-CoV PL pro s may be near the catalytic triad''s cysteine residue due to its competitive pattern of inhibition Chou et al., 2008) . Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin

title:
  Porcine epidemic diarrhea virus papain-like protease 2 can be noncompetitively inhibited by 6-thioguanine

abstract:
  Porcine epidemic diarrhea virus (PEDV) is a coronavirus (CoV) discovered in the 1970s that infects the intestinal tract of pigs, resulting in diarrhea and vomiting. It can cause extreme dehydration and death in neonatal piglets. In Asia, modified live attenuated vaccines have been used to control PEDV infection in recent years. However, a new strain of PEDV that belongs to genogroup 2a appeared in the USA in 2013 and then quickly spread to Canada and Mexico as well as Asian and European countries. Due to the less effective protective immunity provided by the vaccines against this new strain, it has caused considerable agricultural and economic loss worldwide. The emergence of this new strain increases the importance of understanding PEDV as well as strategies for inhibiting it. Coronaviral proteases, including main proteases and papain-like proteases, are ideal antiviral targets because of their essential roles in viral maturation. Here we provide a first description of the expression, purification and structural characteristics of recombinant PEDV papain-like protease 2, moreover present our finding that 6-thioguanine, a chemotherapeutic drug, in contrast to its competitive inhibition on SARS- and MERS-CoV papain-like proteases, is a noncompetitive inhibitor of PEDV papain-like protease 2.


id: cord-337645-t6py0oyw
author: Yin, Jiechao
date: 2010-10-14
txt: ./txt/cord-337645-t6py0oyw.txt
cache: ./cache/cord-337645-t6py0oyw.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354210007448
doi: 10.1016/j.antiviral.2010.10.002
summary:
  Though S protein was not solubilized by cold non-ionic detergents, this behavior was unchanged when cholesterol was depleted from viral membrane by methyl-β-cyclodextrin (MβCD) and the protein did not comigrate with cellular DRM marker proteins in flotation analyses. A functional analysis suggests that cholesterol depletion affects a post-adsorption step in the virus entry process that requires membrane rearrangements. As cholesterol depletion from TGE virions results in a reduction of viral infectivity (Ren et al., 2008) , we were interested to find out whether the surface protein S that mediates virus entry is localized in DRMs. For this purpose, we analyzed whether the TGEV S protein is resistant to solubilization by Triton X-100 at 4 • C. This result indicates that the surface protein of TGEV is arranged in the viral envelope in a detergent-resistant way that is not affected by cholesterol depletion.

title:
  Cholesterol is important for a post-adsorption step in the entry process of transmissible gastroenteritis virus

abstract:
  Cholesterol is a major constituent of detergent-resistant membrane microdomains (DRMs). We localized transmissible gastroenteritis virus (TGEV) spike (S) protein in DRMs in the viral envelope. Though S protein was not solubilized by cold non-ionic detergents, this behavior was unchanged when cholesterol was depleted from viral membrane by methyl-β-cyclodextrin (MβCD) and the protein did not comigrate with cellular DRM marker proteins in flotation analyses. Therefore, the S protein is not anchored in the viral membrane DRMs as they are known to occur in the plasma membrane. Cholesterol depletion from viral membrane may not affect the adsorption process as neither the sialic acid binding activity nor the binding to aminopeptidase N was reduced post-MβCD treatment. Reduced infectivity of cholesterol-depleted TGEV was observed only when the adsorption process occurred at 37 °C but not when the virus was applied at 4 °C. Cholesterol is important for a post-adsorption step, allowing membrane rearrangements that facilitate virus entry.


id: cord-348401-x2q9vyf2
title: Middle East respiratory syndrome coronavirus infection is inhibited by griffithsin
author: Millet, Jean K.
date: 2016-07-15
txt: ./txt/cord-348401-x2q9vyf2.txt
cache: ./cache/cord-348401-x2q9vyf2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27424494/
doi: 10.1016/j.antiviral.2016.07.011
summary:
  The MERS-CoV spike protein is a main determinant of virus entry into host cells as it mediates both binding to the DPP4 (dipeptidyl peptidase 4) receptor and fusion of the viral envelope with host cell membrane (Millet and Whittaker, 2014; Raj et al., 2013) . Immunofluorescence assay of MERS-CoV-infected Huh-7, MRC-5, and Vero-81 cells in presence of increasing concentrations of griffithsin. In all conditions, cells were infected with MERS-CoV strain EMC/2012 at an m.o.i. of 10, with griffithsin (1 mg/mL) added or not at different steps during virus entry. Because we have performed our assay using high m.o.i. and a short infection time, these results show the strong inhibitory activity of griffithsin on early steps of the MERS-CoV viral cycle. To better define which stage in the virus life cycle griffithsin acts on, we performed an infection assay using authentic MERS-CoV with griffithsin present at different times during viral entry steps (Fig. 4A) .

abstract:
  Highly pathogenic human coronaviruses associated with a severe respiratory syndrome, including Middle East respiratory syndrome coronavirus (MERS-CoV), have recently emerged. The MERS-CoV epidemic started in 2012 and is still ongoing, with a mortality rate of approximately 35%. No vaccine is available against MERS-CoV and therapeutic options for MERS-CoV infections are limited to palliative and supportive care. A search for specific antiviral treatments is urgently needed. Coronaviruses are enveloped viruses, with the spike proteins present on their surface responsible for virus entry into the target cell. Lectins are attractive anti-coronavirus candidates because of the highly glycosylated nature of the spike protein. We tested the antiviral effect of griffithsin (GRFT), a lectin isolated from the red marine alga Griffithsia sp. against MERS-CoV infection. Our results demonstrate that while displaying no significant cytotoxicity, griffithsin is a potent inhibitor of MERS-CoV infection. Griffithsin also inhibits entry into host cells of particles pseudotyped with the MERS-CoV spike protein, suggesting that griffithsin inhibits spike protein function during entry. Spike proteins have a dual function during entry, they mediate binding to the host cell surface and also the fusion of the viral envelope with host cell membrane. Time course experiments show that griffithsin inhibits MERS-CoV infection at the binding step. In conclusion, we identify griffithsin as a potent inhibitor of MERS-CoV infection at the entry step.


