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Open Access

Drug Discovery Strategies for SARS-CoV-2

Zeenat A. Shyr, Kirill Gorshkov, Catherine Z. Chen and Wei Zheng
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 127-138; DOI: https://doi.org/10.1124/jpet.120.000123
Zeenat A. Shyr
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
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Kirill Gorshkov
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
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Catherine Z. Chen
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
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Wei Zheng
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
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    Fig. 1.

    SARS-CoV-2 spike (S) protein binds the cell surface receptor ACE2 on host cells. Viral genome is delivered into the host cytosol by 1) directly fusing with the plasma membrane after being cleaved and activated by the serine protease TMPRSS2 or 2) using the host cell’s endocytic machinery in which the endocytosed virions are subjected to an activation step in the endosome. The viral genome also functions as the messenger RNA, which is translated into proteins, such as 3CLPro, papain-like cysteine protease (PLpro), and RdRp, by host cell machineries. The SARS-CoV-2 genome also encodes the structural proteins (S), envelope (E), membrane (M), and nucleocapsid (N). RdRP is essential for viral replication and therefore is an attractive target for anti–SARS-CoV-2 drugs. Drugs that are currently in clinical trials are shown here in red, along with their targets of viral life cycle or viral-host interactions. Figure created in BioRender.

Tables

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    TABLE 1

    High-throughput drug repurposing screens against SARS-CoV-2

    Cell lineAssay typeStrain of SARS-CoV-2Library screenedReference
    Caco-2CPEUnspecified5632 compounds, including 3488 compounds that have undergone clinical investigationsaB. Ellinger et al., preprint, DOI: https://doi.org/10.21203/rs.3.rs-23951/v/v1
    Vero E6Primary screen: CPE
    Follow-up: N protein immuno-fluorescence
    HKU-001a in 1’ screen USA-WA1/2020 for follow-upLOPAC 1280 and ReFRAME libraryaL. Riva et al., preprint, DOI: https://doi.org/10.1101/2020.04.16.044016
    Vero E6CPEBavPat1 strainPrestwick Chemical Library (1520 approved drugs)F. Touret et al., preprint, DOI: https://doi.org/10.1101/2020.04.03.023846
    • CPE, cytopathic effect.

    • ↵a Proprietary library.

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    TABLE 2

    Clinical therapies for COVID-19

    Compound/treatmentTargetPhaseClinicalTrials.gov identifierApproved for other clinical treatmentStatus
    Camostat mesilateSerine proteases, e.g., TMPRSS2Phase 1/2NCT04321096Acute pancreatitis (Japan)Ongoing
    ChlorpromazineClathrin-mediated endocytosisPhase 1/2NCT04354805Schizophrenia, manic depression, nausea, anxietyNot yet recruiting
    Phase 3NCT04366739Not yet recruiting
    Ciclesonide, an inhaled corticosteroidViral nonstructural protein 15 encoding an endonuclease and host processPhase 2NCT04330586Asthma and allergic rhinitis (Schaffner and Skoner, 2009)Not yet recruiting
    Favipiravir (Avigan) with tocilizumabRdRpNot applicableNCT04310228Influenza (Japan)Ongoing
    IL-6
    Hydroxychloroquine and chloroquineAntiviral properties unclearVariousMultipleMalaria, autoimmune diseases (e.g., lupus, rheumatoid arthritis)Varies
    Interferon-α1b nasal dropsHost immune response to virusPhase 3NCT04320238NoneOngoing
    IvermectinViral transport into host nucleusVariesMultipleAntiparasiticOngoing
    Lopinavir + ritonavir (Kaletra)3CLproPhase 4NCT04252885HIVOngoing; preliminary results show no benefit beyond standard care (Baden and Rubin, 2020)
    Lopinavir-ritonavir + ribavirin and interferon beta-1b3CLpro, viral polymerase, host immune response to virusPhase 2NCT04276688HIVCompleted; significant improvement in outcomes (Hung et al., 2020)
    NafamostatSerine proteasePhase 1NCT04352400Pancreatitis (Japan and Germany)Not yet recruiting
    NiclosamideViral and host processesPhase 2 and 3NCT04345419Anthelminthic drugNot yet recruiting
    NitazoxanideViral and host processesVariousMultipleAntiparasitic drugOngoing
    RemdesivirRdRpPhase 3NCT04257656HIVTerminated
    NCT04252664Terminated
    NCT04292899Ongoing
    NCT04280705Ongoing
    Tocilizumab or sarilumaubHuman mAb that inhibits the IL-6 pathway by binding and blocking the IL-6 receptorVariousMultipleMultiple, including chimeric antigen receptor T cell–induced cytokine release syndrome, other autoimmune conditions (Barlow et al., 2020)Ongoing
    Umifenovir (Arbidol)Viral membrane fusion of influenza a and bPhase 4NCT04260594Influenza (Russia and China)Not yet recruiting
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    TABLE 3

    Potential vaccines in clinical trials for COVID-19 as of June 29, 2020

    Sources: who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines; clinicaltrials.gov; clinicaltrialsregister.eu.

    Vaccine categoryVaccine typeVaccine developerPhaseVaccine identifier
    DNA basedDNA plasmid + electroporationInovio PharmaceuticalsPhase 1NCT04336410
    DNA vaccine, GX-19Genexine ConsortiumPhase 1NCT04445389
    Inactivated virusInactivatedBeijing Institute of Biologic ProductsPhase 1/2ChiCTR2000032459
    InactivatedWuhan Institute of Biologic ProductsPhase 1/2ChiCTR2000031809
    InactivatedSinovac Research & Development Co., LtdPhase 1/2NCT04352608
    Phase 1/2NCT04383574
    InactivatedChinese Academy of Medical SciencesPhase 1/2NCT04412538
    Nonreplicating viral vectorAdenovirus type 5CanSino Biologic Inc; preliminary results (Zhu et al., 2020)Phase 1NCT04313127
    Beijing Institute of BiotechnologyPhase 2ChiCTR2000031781
    ChAdOx1-SUniversity of Oxford/AstraZenecaPhase 3 Phase 2/3ISRCTN89951424
    Phase 2/32020-001228-32
    Phase 1/2NCT04400838
    Phase 1/22020-001072-15 NCT04324606
    AdenoviralGamaleya Research InstitutePhase 1 Phase 1/2NCT04436471
    NCT04437875
    Adeno basedChinese Academy of Medical SciencesPhase 2NCT04341389 NCT04412538
    Protein subunitRecombinant SARS-CoV-2 trimeric S protein subunitClover Biopharmaceuticals Inc./GSK/DynavaxPhase 1NCT04405908
    Recombinant protein (RBD dimer)Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd/The Second Affiliated Hospital of Chongqing Medical University/Beijing Chao Yang HospitalPhase 1NCT04445194
    Full length recombinant SARS CoV-2 glycoproteinnanoparticle vaccine adjuvanted with Matrix MNovavaxPhase 1/2NCT04368988
    RNAMessenger RNA in lipid nanoparticleModerna/NIH/NIAID; related preclinical study (Corbett et al., 2020)Phase 1 Phase 2NCT04283461 NCT04405076
    Messenger RNA in lipid nanoparticleBioNTech/Fosun Pharma/PfizerPhase 1/22020-001038-36
    Phase 1NCT04368728
    mRNACurevacPhase 1NCT04449276
    mRNAPeople’s Liberation Army (PLA) Academy of Military Sciences/Walvax BiotechPhase 1ChiCTR2000034112
    Self-amplifying RNA in lipid nanoparticleImperial College LondonPhase 1ISRCTN17072692
    • GSK, GlaxoSmithKline; NIAID, National Institute of Allergy and Infectious Diseases; NIH, National Institutes of Health.

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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleMinireview

SARS-CoV-2 Drug Discovery

Zeenat A. Shyr, Kirill Gorshkov, Catherine Z. Chen and Wei Zheng
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 127-138; DOI: https://doi.org/10.1124/jpet.120.000123

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Research ArticleMinireview

SARS-CoV-2 Drug Discovery

Zeenat A. Shyr, Kirill Gorshkov, Catherine Z. Chen and Wei Zheng
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 127-138; DOI: https://doi.org/10.1124/jpet.120.000123
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  • Article
    • Abstract
    • Introduction
    • Overview of SARS-CoV-2 Genome and Protein Constituents
    • Viral Entry Through the Binding of SARS-CoV-2 Spike Proteins to Angiotensin Converting Enzyme 2 Receptor
    • SARS-CoV-2 Has Multiple Viral Entry Mechanisms
    • Drug Development Strategies
    • SARS-CoV-2 Viral Entry Inhibitors
    • Viral Replication Inhibitors
    • Host Cell and Viral Targets for Antiviral Drug Development
    • Prophylactic Treatment of SARS-CoV-2 Infection
    • Other Treatments in Clinical Trials for COVID-19
    • Vaccines for SARS-CoV-2
    • Perspectives and Conclusion
    • Authorship Contributions
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