key: cord-0985184-us41gce3
authors: Srivastava, Vartika; Ahmad, Aijaz
title: New perspective towards therapeutic regimen against SARS-CoV-2 infection
date: 2021-05-26
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.05.009
sha: f0df71c39c44022e80006b732d0de2b5116320ec
doc_id: 985184
cord_uid: us41gce3

The ongoing enormous loss of human life owing to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to a global crisis ranging from the collapse of health – care systems to socio-economic instability. As SARS-CoV-2 is a novel virus, very little information is available from researchers and therefore, a rigorous effort is required to decode its pathogenicity. There are no licenced treatment options available for treating SARS-CoV-2 infections and the development of a new antiviral drug targeting coronavirus cannot happen soon. Consequently, drug repurposing is a promising solution for combating the present pandemic. In this review, we have thoroughly discussed all the proteins encoded by the SARS-CoV-2 genome; their importance in pathogenicity and their potential role in drug discovery. Also, the budding threat of co-infections by other pathogenic microbes has been highlighted. Furthermore, the advances made in the medicinal field for the treatment and prevention of this viral infection is explained. Altogether, this review will provide some insightful discussions about this infectious disease and will meet certain of the knowledge gaps which exist by presenting an exhaustive and extensive scientific report on the ongoing mission for COVID-19 drug discovery.

4 infections [14] . Malaria treatments options, namely, chloroquine and hydroxychloroquine were initially reported to be an effective option against COVID-19 [15] ; however, the results from clinical trial (NCT04332991) [16] and prophylaxis data recorded by Boulware and coworkers [17] were not promising. Additionally, the withdrawal of chloroquine and hydroxychloroquine from chief investigations denotes the termination of attempts to repurpose these drugs for combating SARS-CoV-2 infection [18] . Remdesivir, an unsuccessful Ebola drug, has also shown potential and is being repurposed for SARS-CoV-2 infections; however, additional clinical trials are still ongoing to ensure the effectiveness of this drug in COVID-19 patients. Despite all this, a standard treatment for SARS-CoV-2 infections is still lacking and increasing incidences of asymptomatic infections, excessive transmissibility, and a long incubation period have made COVID-19 a competent and challenging pathogen which is very difficult to contain.

Most importantly, the occurrence of microbial co-infections in COVID-19 patients complicates the situation by increasing the hitches in management of diagnosis of and prognosis for SARS-CoV-2. Therefore, clinicians cannot ignore the high chance and risk of co-infections caused by all groups of microbes, bacteria, viruses and fungi among patients that may further result in serious disease symptoms and raise the mortality rate [19] .

However, it cannot be denied that coinfected microorganisms can bring hope for developing new strategies against SARS-CoV-2 infection. Therefore, in the present review we have highlighted this crucial aspect to emphasise the importance of microbial coinfection in SARS-CoV-2 infection.

Although there are no targeted antiviral agents available for treatment of novel SARS-CoV-2, a remarkable amount of research is in progress to find potential treatments that can save humankind and develop vaccines that can secure our future. This review aims to strengthen Furin-like protease present in the host cell cleaves S glycoproteins into two sub-units, namely the S1 part (N-terminal), responsible for virus-host receptor binding and the S2 part (Cterminal), which mediates virus-cell membrane fusion in transmitting host cells [22, 23] .

Therefore, the process of SARS-CoV-2 infection starts with the binding of S1-receptorbinding domain (S1-RBD) to the cell membrane receptors of the host cell, causing a structural change in the S2 part which results in fusion and the entry of the viral particle into the target cell [24, 25] interact with M proteins to form the viral envelope and accounts for SARS-CoV-2 assembly, budding and pathogenesis [26, 28] . They are found to be highly conserved among the beta coronaviruses. There are predominantly two structural domains: a hydrophobic domain and a charged cytoplasmic tail. The presence of heme agglutinin-esterase protein has been reported in some of the coronaviruses.

The second group of proteins, non-structural proteins (NSP), play a vital role and control the assembly of the viral particle as well as its escape from the host defence system. The RNA genome that encodes these proteins is replicase complex, containing two ORFs (ORF1a and ORF1b), complete expression of which is accomplished via ribosomal frameshifting [32] .

The translation of ORF1a and ORF1b produces two huge overlapping polyproteins, pp1a and pp1ab. These polyproteins are then cleaved into 16 mature smaller proteins by the papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro), also known as the main protease (Mpro). From 16 proteins, the first 11 are transcribed from ORF1a and the remaining five from ORF1b [20, 23] . A summary of the non-structural proteins as well as and their roles, are outlined in Table 1 below: 

There are eight accessory proteins reported to date. While they are not essential for replication (suggested by in vitro studies), some of them are proved to be important for virushost interactions. The group include ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8a,

ORF8b, and ORF9b [51] . The details of accessory proteins reported in SARS CoV-2 and their functions are outlined in Table 2 below: whereas 62 out of 806 (8%) cases of bacterial/fungal co-infection were reported. These patients were put on broad-spectrum antibiotic treatment, with 72% of cases getting antibacterial therapy alone [67] . Co-infections with bacteria such as S. pneumoniae, followed by K. pneumoniae and H. influenzae were commonly reported in SARS-CoV-2 patients [68] .

There are also studies reporting SARS-CoV-2 patients suffering with severe invasive pulmonary aspergillosis [69, 70] . Among SARS-CoV-2 patients the proportion of bacterial co-infection was highest, followed by bacterial-viral, viral-fungal and viral-bacterial-fungal co-infections [68] .

Altogether rates of co-infections in SARS-CoV-2 patients are increasing above what was previously reported. Although the number is small, the chance of co-infection is higher, which needs to be investigated in detail.

SARS-CoV-2 infection has already proven to be a devastating disease worldwide. Therefore, the most urgent timely requirement now is to advance treatment options against this disease. host-specific receptors such as Angiotensin-converting enzyme 2 (ACE2), which serves as an entry point for CoVs.

Spike protein is a crucial structural protein of CoVs and forms a trimeric structure on the surface and mediates the invasion and virulence of the virus. The S protein is also responsible for activating the host immune response toward the viral particle [71] . Therefore, targeting S proteins or specific host cell receptors is a valuable therapeutic strategy for antiviral drug development.

The receptor-binding domain (RBD) is the main target for designing drugs against SARS-CoV-2. Available literature suggested a few potential targets that hamper S1-RBD: ACE-2 binding and therefore, block the entry of SARS-CoV. The inhibitors are: OC43-HR2P

(peptide derived from HCoV-OC43) showed pan-CoV fusion inhibition property [72] , chloroquine (antimalarial agent, elevates endosomal pH and modifies ACE-2 binding site, thus inhibiting virus receptor binding) [73] , SSAA09E2 (block the S-ACE2 binding), SSAA09E1 (blocks viral entry), SSAA09E3 (inhibits host and viral cell membrane fusion) [74] , the S230 antibody nullifies various isolates of SARS-CoV [75] , m396 (monoclonal antibody) competes for RBD [76] , 80R and CR301 (monoclonal antibodies) are spikespecific antibodies that nullify viral infection by preventing S-ACE-2 binding [77] .

The other structural proteins in SARS-CoV-2 are E protein and N protein. E protein (Echannel) owns the central function for maintaining the structural and viral pathogenicity, whereas NRBD and CRBD are the important domains of Cov N protein and they are required for an efficient host-viral interaction. Therefore, collectively, these structural proteins can be thoroughly targeted for antiviral drug discovery [78] . active site consisting of the cys-his dyad responsible for protease activity [79] . It releases mature Nsp4-Nsp16 by cleaving Nsps present downstream at 11 sites, and facilitates production of advanced protein-mediating replication/transcription complex [80, 81] . Due to important catalytic activity 3CLpro is an attractive target for developing antiviral drugs and mainly small-molecules and peptide inhibitors are used for screening [82] .

An in silico study [83] indicated that antibacterial medications (oxytetracycline, demeclocycline, doxycycline and lymecycline), conivaptan (used for hyponatremia) and antihypertensive drugs (nicardipine and telmisartan) were inhibitors of 3CLpro. Other In silico studies suggested potential 3CLpro inhibitors among presently available drugs (aprepitant, icatibant, colistin, bepotastine, perphenazine, valrubicin, epirubicin, and caspofungin. These drugs also bind to the antiretroviral-binding site on SARS-CoV [84] . Small molecules, phthalhydrazide-substituted ketoglutamine analogs, arylboronic acids, thiophenecarboxylate and quinolinecarboxylate derivatives have been explored and proved to inhibit 3CLpro [85] .

The inhibitors of HIV protease, lopinavir and ritonavir also inhibit 3CLpro [84] . Various natural products and their derivatives have been reported to show high binding affinity to 3CLpro [83] .

These function by slicing the N-terminus of the replicase poly protein (PP) and produce three NSPs (NSP1, NSP 2, and NSP 3) which are critical for virus replication [86] . Being vital enzymes for CoV replication and host infection, PLpro are becoming a well-accepted focus for drug advances against SARS-CoV-2.

However, there is no candidate yet approved by the FDA as a drug. Zinc and its conjugates at higher doses were found to inhibit PLpro [87] . Benzodioxole [88] and a new lead compound (6577871) [89] were identified as strong inhibitors by in silico studies. Lopinavir-ritonavir combinations are also being used for treating SARS-CoV-2 infection [90] . Wu and coworkers (2020) have discussed a series of available drugs as well as natural products with strong affinity towards PLpro. The major drugs include antibacterial drugs (chloramphenicol, cefamandole and tigecycline), and antiviral drugs (ribavirin, valganciclovir and thymidine) [83] . terminus [91] . However, in previous beta coronavirus epidemics Nsp12-RdRp was considered as a significant drug target because inhibition of this enzyme significantly reduces toxicity and side effects in host cells [92] . Remdesivir and Ribavirin (antiviral agents) have the potential to serve as drug candidates that can block this enzyme [93] . Several other existing compounds are also presented as probable inhibitors of this enzyme, namely, itraconazole, novobiocin, chenodeoxycholic acid, cortisone, idarubicin, silybin and pancuronium bromide [83] .

: Helicase (NSP13) is a vital protein which has a critical role in the viral central dogma, with an ability to untangle double-stranded DNA and RNA in an NTPdependent manner [94] . The SARS-Nsp13 sequence has been found conserved, and is a vital factor for the replication of CoV. Therefore, NSP13 has been recognized as a potential druggable target [95, 96] . However, toxicity due to the non-specificity of inhibitors is considered to be the biggest hurdle [97] . On the basis of in silico studies drugs namely, J o u r n a l P r e -p r o o f lymecycline, cefsulodine, rolitetracycline, itraconazole and saquinavir were expected to be NTPase inhibitors [83] .

Apart from the abovementioned drug targets, some NSPs that are critical players in viral RNA synthesis and replication, namely: NSP3b, NSP3e, NSP6, NSP7-8 complex, NSP9, NSP10, NSP12 and NSP14-16, need further investigation for anti-viral drug discovery [60] .

The SARS-CoV virulence factors that help the virus to escape the host immune system as well as interfere with the host's innate immunity are Nsp1, Nsp3c and ORF7. (a) Nsp1 inhibits type-I interferon production and is also responsible for degradation of the host mRNA [98, 99] . (b) Nsp3c supports the in virus to resisting host innate immunity by binding with host's ADP-ribose [100] . (c) ORF7a binds and inhibits activity of the bone marrow matrix antigen 2 (BST-2) by blocking its glycosylation [54] . These effects of the virulence factors therefore advocate their potential for anti-viral drug advances.

Many studies have already unambiguously proved ACE2 as a receptor for S-RBD of coronavirus [101] . Recent work proves that the SARS-CoV-2 host receptor is constant among SARS-CoVs, therefore, the sequence of S-RBD in SARS-CoV-2 is similar, and central linking exists between the RBD receptor-binding motif and ACE2 receptors [102] . Therefore, 

To date, no medication has been approved for treating SARS-Cov-2 infection. Prevailing therapeutic options are not effective against this infection; however, a variety of possible treatments options are being explored by scientists [103] . In this situation the best way to tackle this infection will be drug repurposing. Considering the information obtained from genomic sequence along with in silico protein modelling, researchers have been working hard to find a way to defeat this menace.

Recently published work has recognized the interaction of SARS CoV-2 proteins with 332 human proteins. Out of these 332 protein-protein interactions, 66 were targetable by different antiviral compounds. All these compounds were further screened by multiple viral assays, Severity of SARS CoV-2 infection is mostly among elderly patients, which is may be due to weak immune response due to the age factor. Therefore, adapting ways to boost innate immunity against viral attack shows great potential. A previous study has shown a promising J o u r n a l P r e -p r o o f role of macrophages and NK cells in the clearance of SARS-CoV after their pulmonary migration and thereby raising the levels of chemokines and cytokines [105] . There are several multinational companies who are utilizing this approach and aiming to reuse their NK-based products to combat COVID-19 infection. The most promising step has been taken by Cellularity (a USA-based company) by developing CYNK-001. Also, Type I interferons, used alone or in combination, give a broad-spectrum protection against viral infections including MERS-CoV [106] and SARS-CoV [107] .

The SARS viral infection is majorly correllated with a high inflammatory response in the respiratory tract [108, 109] . Hence, targeting mesenchymal stem cells (MSC) for therapeutic use in viral treatment has been proposed by various researchers, as these cells are acknowledged to exert anti-inflammatory responses and initiate the tissue repair mechanism [110] . The purpose of MSCs in treatment of COVID-19 pneumonia is still being investigated.

Similarly, intravenous immunoglobulin (IVIG) is gaining attention for the treatment [111] .

However, a more to the point approach for SARS-CoV treatment could be generation of surface specific epitope-targeting neutralizing antibodies [112] . Unfortunately, this is a timeconsuming process and requires a lot of effort. The anti-C5a monoclonal antibodies may attenuate the degree of lung damage caused by COVID-19 by lowering the neutrophil influx and vascular leakage into the alveolar space [113] . When blocking the interleukin (IL)-6 pathway, as previously reported, a high level of IL-6 in blood rapidly reduces lung elasticity, resulting in acute bronchoalveolar inflammation. Thus, specific blocking of the IL-6regulated signalling cascade may be considered as a valuable approach towards treatment [114] . The drug thalidomide which shows anti-inflammatory and anti-fibrotic effects, may reduce lung injury, and therefore it is also in the pipeline for COVID-19 patients. Moreover, clinical evaluation of methylprednisolone (a synthetic glucocorticoid) and fingolimod (an increases their likelihood of forming an effective vaccine. However, the dominating immunogenicity for the vector will always be a concern [115] .

Researchers are also putting effort into evaluating the efficacy of certain genetically modulated artificial antigen-presenting cells (aAPCs) specifically presenting the SARS-CoV structural proteins (conserved domains), and probably helping cells to endure the penetration of COVID-19 [116] . Table 3 summarises the drugs that are in clinical trial which help in combating novel SARS-CoV2 infection. Data not available Ribavirin [118] ; broad-spectrum antiviral, primarily used for treatment of hepatitis C.

Inhibiting the viral protease

Ivermectin [120] (Stromectol/Soolantra cream); drug used to treat parasitic infections.

J o u r n a l P r e -p r o o f with antigen-specific cytotoxic T cells [140] NCT04299724 and NCT04276896

Owing to the high morbidity and mortality associated with SARS-CoV-2 infection there is an urgent need for mitigation methods, and one of such method is vaccine development.

Thorough research suggested that there is a significant sequence homology between SARS-CoV-2 and other beta-coronaviruses (SARS and MERS). The vaccines identified for these lethal coronaviruses can therefore be of high value in preparing vaccines against SARS-CoV-2 [141] .

The viral S-protein based vaccine development approach has drawn the attention of many scientists in the fight against COVID-19. These subunit vaccines can elicit protective immunity, producing higher neutralizing antibodies as compared with DNA-based S protein vaccines, live-attenuated coronavirus and full-length S protein [142] . Presently, 188 wellestablished patents are present in the Chemical Abstracts Service (CAS) collection related to anti-SARS and anti-MERS vaccines. Most of them are associated with the S protein subunit vaccine and vaccines specifically targeting S-RBD [90] . Therefore, the preferred target for vaccine development against beta-coronaviruses is the S protein/gene, and applying the same strategy and knowledge will be beneficial in developing vaccines against SARS-CoV-2 [23, 141] . Table 4 comprehends the list of SARS and MERS vaccines that have been patented.

Moreover, the prospect of short-term immunogenicity resulting from neutralising antibodies should be addressed. Along with B cell response, T cell response should also be considered, J o u r n a l P r e -p r o o f because these responses are protective and persistent in humans. Strategies for augmenting immunogenicity and preventing undesired side effects should be explored [141] . 

ICTV Master Species List 2009-v10, International Committee on Taxonomy of Viruses

Nidovirales: evolving the largest RNA virus genome

Virology: Coronaviruses"

Global patterns in coronavirus diversity

Epidemiology, genetic recombination, and pathogenesis of coronaviruses

A novel coronavirus from patients with pneumonia in China

An updated estimation of the risk of transmission of the novel coronavirus (2019-nCov)

SARS (severe acute respiratory syndrome)

Clinical Features, Middle East Respiratory Syndrome (MERS)

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries

ORCHID: Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease

A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19

Chloroquine and hydroxychloroquine for COVID-19: Perspectives on their failure in repurposing

The microbial coinfection in COVID-19

The proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the cause of COVID-19

Role of nonstructural proteins in the pathogenesis of SARS-CoV-2

Neutralizing antibodies against SARS-CoV-2 and other human Coronaviruses

The molecular biology of coronaviruses

Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling

Nsp3 of coronaviruses: structures and functions of a large multi-domain protein

Times of India

Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray

Evolutionary analysis of SARS-CoV-2: how mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy

Coronavirus NSP6 restricts autophagosome expansion

The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension

Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV

Crystal Structure of the SARS-CoV-2 Non-structural Protein 9

Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex

Coronavirus nsp10/nsp16 methyltransferase can be targeted by nsp10-derived peptide in vitro and in vivo to reduce replication and pathogenesis

Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites

Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

The coronavirus proofreading exoribonuclease mediates extensive viral recombination bioRxiv

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with Sadenosylmethionine

Crystal structure and functional analysis of the sars-coronavirus RNA cap 2'-O-methyltransferase nsp10/nsp16 complex

Accessory proteins of SARS-CoV and other coronaviruses

SARS-CoV-2 and ORF3a: Nonsynonymous Mutations, Functional Domains, and Viral Pathogenesis

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

Severe acute respiratory syndrome coronavirus ORF7a inhibits bone marrow stromal antigen 2 virion tethering through a novel mechanism of glycosylation interference

The ORF7b protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is expressed in virus-infected cells and incorporated into SARS-CoV particles

Severe acute respiratory syndrome (SARS) coronavirus ORF8 protein is acquired from SARS-related coronavirus from greater horseshoe bats through recombination

Attenuation of replication by a 29 nucleotide deletion in SARS-coronavirus acquired during the early stages of humanto-human transmission

Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2. mBio

Tom70 mediates activation of interferon regulatory factor 3 on mitochondria

A SARS-CoV-2-Human protein-protein interaction map reveals drug targets and potential drug-repurposing

Co-infections among patients with COVID19: The need for combination therapy with non-anti-SARS-CoV-2 agents?

Rates of co-infection between SARS-CoV-2 and other respiratory pathogens

Coinfection of SARS-CoV-2 and multiple respiratory pathogens in children

Co-infection with SARS-CoV-2 and influenza A virus

Coinfection of influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), The Pediatric

SARS-CoV-2 and influenza virus co-infection

Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing

Co-infection with respiratory pathogens among COVID-2019 cases

Prevalence of putative invasive pulmonary aspergillosis in critically ill COVID-19 patients

COVID-19 associated pulmonary aspergillosis

Structure, Function, and Evolution of Coronavirus Spike Proteins

A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms

Unexpected receptor functional mimicry elucidates activation of coronavirus fusion

Structure of severe acute respiratory syndrome coronavirus receptor-binding domain complexed with neutralizing antibody

The spike protein of SARS-CoV-a target for vaccine and therapeutic development

Drug targets for corona virus: A systematic review

Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors

Mechanism of the maturation process of SARS-CoV 3CL protease

The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity

An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines

Mechanism of the maturation process of SARS-CoV 3CL protease

Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity

Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition

X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases

Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: Design, synthesis, proteinligand X-ray structure and biological evaluation

Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of

Lopinavir/Ritonavir for the treatment of COVID-19 infected Pneumonia monitored by quantitative RT-PCR

SARS-CoV ORF1b-encoded nonstructural proteins 12-16: replicative enzymes as antiviral targets

Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-CoV)

Research and development on therapeutic agents and vaccines for COVID-19 and related human Coronavirus Diseases

Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5′-triphosphatase activities

Differential inhibitory activities and stabilisation of DNA aptamers against the SARS coronavirus helicase

Isolation of inhibitory RNA aptamers against severe acute respiratory syndrome (SARS) coronavirus NTPase/Helicase

Understanding helicases as a means of virus control

Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by J o u r n a l P r e -p r o o f promoting host mRNA degradation

Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells

Extensive positive selection drives the evolution of nonstructural proteins in lineage C betacoronaviruses

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS

Treatment options for COVID-19: The reality and challenges

A Large-scale drug repositioning survey for SARS-CoV-2 antivirals

Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+ T Cells Are Important in Control of SARS-CoV Infection

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Treatment of SARS with human interferons

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Potential application of mesenchymal stem cells in acute lung injury

A Review of SARS-CoV-2 and the ongoing clinical trials

Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2

Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio

Positive RT-PCR Test Results in Patients Recovered From

Favipiravir: A new and emerging antiviral option in COVID-19

Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review)

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19

Antiviral activity and safety of Darunavir/Cobicistat for the treatment of COVID-19

Human recombinant soluble ACE2 in severe COVID-19

Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial

Can Natural Killer Cells be a principal player in anti-SARS-CoV-2 immunity?

Interferons in the therapy of severe Coronavirus infections: A critical analysis and recollection of a forgotten therapeutic regimen with interferon beta

Mesenchymal stem cells in COVID-19: A journey from bench to bedside

The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease J o u r n a l P r e -p r o o f 2019: a randomized placebo-controlled double-blind clinical trial

Neutralizing antibodies for the treatment of COVID-19

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial

Current evidence of Interleukin-6 signaling inhibitors in patients with COVID-19: A systematic review and meta-analysis

Thalidomide-Revisited: Are COVID-19 patients going to be the latest victims of yet another theoretical drug-repurposing? Front Immunol

Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial

Asymptomatic SARS-CoV-2 infection in two patients with multiple sclerosis treated with fingolimod

Efficacy and tolerability of bevacizumab in patients with severe Covid-19

Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice

Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: A preliminary report of an open-label, Phase 1 clinical trial

Oxford COVID Vaccine Trial Group. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Nanotechnology against the novel coronavirus (severe acute respiratory syndrome coronavirus 2): diagnosis, treatment, therapy and future perspectives Nanomedicine

Investigating virological, immunological, and pathological avenues to identify potential targets for developing COVID-19 treatment and prevention strategies. Vaccines (Basel)

Vaccines for SARS-CoV-2: Lessons from other coronavirus strains

Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity

Genomic variance of the 2019-nCoV coronavirus