key: cord-0716615-euhw5pge authors: Su, Haixia; Xu, Yechun; Jiang, Hualiang title: Drug Discovery and Development Targeting the Life Cycle of SARS-CoV-2 date: 2021-02-01 journal: nan DOI: 10.1016/j.fmre.2021.01.013 sha: 127e9b6a483cad9b3266668740d0adb2cd431536 doc_id: 716615 cord_uid: euhw5pge A newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the β-coronavirus family and shows high similarities with SARS-CoV. On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-2 a global pandemic, and the disease was named the coronavirus disease 2019 (COVID-19). The ongoing COVID-19 pandemic has caused over 46 million infections and over one million deaths worldwide, and the numbers are still increasing. Efficacious antiviral agents are urgently needed to combat this virus. The life cycle of SARS-CoV-2 mainly includes the viral attachment, membrane fusion, genomic replication, assembly and budding of virions. Accordingly, drug development against SARS-CoV-2 currently focuses on blocking spike protein binding to ACE2, inhibiting viral membrane fusion with host cells, and preventing the viral replication by targeting 3C-like protease, papain-like protease, RNA-dependent RNA polymerase as well as some host-cell proteins. In this review, the advances of drug development in these three major areas are elaborated. In at? the distal edge of the RBD receptor-binding subdomain, blocking the interaction 136 between the RBD and ACE2. H104 demonstrated good antiviral efficacy in animals. In the prophylactic and prophylactic plus therapeutic groups, treatment of H014 at a . 147 In addition to S309, S2M11 developed by Tortorici [29] also targets such an epitope 148 and achieves the antiviral efficacy by a similar mechanism (Fig. 3e ). 358 II (Fig. 11) . It shares features with previously reported 3CLpro of other coronaviruses. The high structure similarity suggests that previously reported 3CLpro inhibitors may and 11b were also determined (Fig. 11 ). An overlay of these complex structures SARS-CoV-2 Cell Entry Depends 582 on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor A pneumonia outbreak associated with a new 585 coronavirus of probable bat origin TMPRSS2 and furin are both essential for 587 proteolytic activation of SARS-CoV-2 in human airway cells SARS-CoV-1 and SARS-CoV-2 from atomic resolution structure and membrane 590 dynamics The spike glycoprotein of the new 592 coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same 593 clade Lysosomal Exocytosis, Exosome Release and 602 Secretory Autophagy: The Autophagic-and Endo-Lysosomal Systems Go 603 Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B A human neutralizing antibody targets the 610 receptor-binding site of SARS-CoV-2 A noncompeting pair of human neutralizing antibodies 612 block COVID-19 virus binding to its receptor ACE2 Human neutralizing antibodies elicited by SARS-CoV-2 614 infection Studies in humanized mice and convalescent 616 humans yield a SARS-CoV-2 antibody cocktail Neutralizing nanobodies bind SARS-CoV-2 spike 618 28 Broad neutralization of SARS-related viruses by 624 human monoclonal antibodies Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor Isolation of potent SARS-CoV-2 neutralizing 629 antibodies and protection from disease in a small animal model Analysis of a SARS-CoV-2-Infected 632 Individual Reveals Development of Potent Neutralizing Antibodies with Limited 633 Convergent antibody responses to SARS-CoV-2 in convalescent individuals Potent neutralization of SARS-CoV-2 in vitro and 637 in an animal model by a human monoclonal antibody Potent neutralizing antibodies 648 from COVID-19 patients define multiple targets of vulnerability Ultrapotent human antibodies protect 651 against SARS-CoV-2 challenge via multiple mechanisms Structural basis for neutralization of SARS-CoV-2 and 653 SARS-CoV by a potent therapeutic antibody Cross-neutralization of SARS-CoV-2 by a 655 human monoclonal SARS-CoV antibody A human monoclonal antibody blocking SARS-CoV-2 657 infection Neutralization of SARS-CoV-2 by Destruction of the 659 Prefusion Spike Engineering human ACE2 to optimize binding 668 to the spike protein of SARS coronavirus 2 Angiotensin-converting enzyme 2 protects from severe 670 acute lung failure A pilot clinical trial of recombinant human 672 angiotensin-converting enzyme 2 in acute respiratory distress syndrome Pharmacokinetics and pharmacodynamics 675 of recombinant human angiotensin-converting enzyme 2 in healthy human subjects Design of ACE2-Based Peptide Inhibitors of 678 SARS-CoV-2 Korendovych IV and DeGrado WF De novo protein design, a retrospective De novo design of potent and selective mimics of IL-2 Design of inhibitors of influenza virus 691 membrane fusion: synthesis, structure-activity relationship and in vitro antiviral activity 692 of a novel indole series Structural basis of influenza virus fusion inhibition by the 694 antiviral drug Arbidol Clinical Features of 69 Cases With Coronavirus Disease 696 2019 in Wuhan, China Effect of Arbidol (Umifenovir) on COVID-19: a 698 randomized controlled trial Nafamostat Mesylate Blocks 700 Activation of SARS-CoV-2: New Treatment Option for COVID-19 The androgen-regulated protease TMPRSS2 703 activates a proteolytic cascade involving components of the tumor microenvironment 704 and promotes prostate cancer metastasis Camostat mesylate against SARS-CoV-2 and 706 COVID-19-Rationale, dosing and safety Identification of the first synthetic inhibitors of 708 the type II transmembrane serine protease TMPRSS2 suitable for inhibition of 709 influenza virus activation Hydroxychloroquine and azithromycin as a Preliminary evidence from a multicenter prospective 714 observational study of the safety and efficacy of chloroquine for the treatment of Low dose of hydroxychloroquine reduces fatality of critically 717 ill patients with COVID-19 Beneficial effects exerted by hydroxychloroquine in treating COVID-19 patients via protecting multiple organs. Sci China Life Sci 2020 Azithromycin in Mild-to-Moderate Covid-19 A pan-coronavirus fusion inhibitor targeting the HR1 domain 723 of human coronavirus spike Inhibition of SARS-CoV-2 (previously 2019-nCoV) 725 infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein 726 that harbors a high capacity to mediate membrane fusion Design of Potent Membrane Fusion Inhibitors against SARS-CoV-2, an Emerging Coronavirus with High Fusogenic Activity Structure of M(pro) from SARS-CoV-2 and discovery of its 735 inhibitors Targeting severe acute respiratory 737 syndrome-coronavirus (SARS-CoV-1) with structurally diverse inhibitors: a 738 comprehensive review Crystal structure of SARS-CoV-2 main protease provides 740 a basis for design of improved alpha-ketoamide inhibitors Feline coronavirus drug inhibits the main 742 protease of SARS-CoV-2 and blocks virus replication GC-376, and calpain inhibitors II, XII 744 inhibit SARS-CoV-2 viral replication by targeting the viral main protease Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease Discovery of Ketone-Based Covalent 749 Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of 750 COVID-19 Structural basis for the inhibition of SARS-CoV-2 main 752 protease by antineoplastic drug carmofur Anti-SARS-CoV-2 activities in vitro of 754 Shuanghuanglian preparations and bioactive ingredients AD The SARS-coronavirus papain-like 757 protease: structure, function and inhibition by designed antiviral compounds Characterization and Noncovalent Inhibition of 760 the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease Crystal structure of SARS-CoV-2 papain-like protease Activity profiling and structures of inhibitor-bound SARS-CoV-2-PLpro protease provides a framework for anti-COVID-19 drug design Structure of the RNA-dependent RNA polymerase from 769 COVID-19 virus Structural basis for inhibition of the RNA-dependent RNA 771 polymerase from SARS-CoV-2 by remdesivir RNA-Dependent RNA Polymerase as a Target 773 for COVID-19 Drug Discovery The antiviral compound remdesivir 777 potently inhibits RNA-dependent RNA polymerase from Middle East respiratory 778 syndrome coronavirus GS-5734) protects African green 780 monkeys from Nipah virus challenge Efficacy and safety of the nucleoside 782 analog GS-441524 for treatment of cats with naturally occurring feline infectious 783 peritonitis Comparative therapeutic efficacy of remdesivir 785 and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Remdesivir and chloroquine effectively inhibit the 788 recently emerged novel coronavirus (2019-nCoV) in vitro Compassionate Use of Remdesivir for Patients 790 with Severe Covid-19 Remdesivir for the Treatment of Covid-19 The ubiquitin-like (UBL), thumb, zinc-finger, and palm domains 875 are shown in yellow, blue, orange, and purple, respectively. The active site is 876 highlighted in red. (b) The binding mode of GRL-0617 GRL-0617 is shown in green sticks. (c) The binding mode of VIR250 (yellow) and 878 VIR251 (magentas) in the SARS-CoV-2 PLpro