Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Matthew D Hall¹, James M Anderson², Annaliesa Anderson³, David Baker⁴, Jay Bradner⁵, Kyle R Brimacombe¹, Elizabeth A Campbell⁶, Kizzmekia S Corbett⁷, Kara Carter⁸, Sara Cherry⁹, Lillian Chiang¹⁰, Tomas Cihlar¹¹, Emmie de Wit¹², Mark Denison¹³, Matthew Disney¹⁴, Courtney V Fletcher¹⁵, Stephanie L Ford-Scheimer¹, Matthias Götte¹⁶, Abigail C Grossman¹, Frederick G Hayden¹⁷, Daria J Hazuda¹⁸, Charlotte A Lanteri¹⁹, Hilary Marston²⁰, Andrew D Mesecar²¹, Stephanie Moore²², Jennifer O Nwankwo²³, Jules O'Rear²⁴, George Painter²⁵, Kumar Singh Saikatendu²⁶, Celia A Schiffer²⁷, Timothy P Sheahan²⁸, Pei-Yong Shi²⁹, Hugh D Smyth³⁰, Michael J Sofia³¹, Marla Weetall³², Sandra K Weller³³, Richard Whitley²², Anthony S Fauci²⁰, Christopher P Austin¹, Francis S Collins², Anthony J Conley²⁰, Mindy I Davis²⁰

Affiliations

¹ National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
² Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
³ Pfizer Vaccine Research and Development, Pfizer, Pearl River, New York, USA.
⁴ University of Washington, Seattle, Washington, USA.
⁵ Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
⁶ The Rockefeller University, New York, New York, USA.
⁷ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁸ Evotec, Lyon, France.
⁹ University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Evrys Bio, Doylestown, Pennsylvania, USA.
¹¹ Gilead Sciences, Foster City, California, USA.
¹² Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
¹³ Vanderbilt University, Nashville, Tennessee, USA.
¹⁴ Scripps Research, Jupiter, Florida, USA.
¹⁵ University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁶ University of Alberta, Edmonton, Alberta, Canada.
¹⁷ University of Virginia, Charlottesville, Virginia, USA.
¹⁸ Merck & Co, Inc, Kenilworth, New Jersey, USA.
¹⁹ Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
²⁰ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
²¹ Purdue University, West Lafayette, Indiana, USA.
²² University of Alabama at Birmingham, Birmingham, Alabama, USA.
²³ 1910 Genetics, Inc, Cambridge, Massachusetts, USA.
²⁴ US Food and Drug Administration, Silver Spring, Maryland, USA.
²⁵ Emory University, Atlanta, Georgia, USA.
²⁶ Takeda California, Inc, San Diego, California, USA.
²⁷ University of Massachusetts Medical School, Worcester, Massachusetts, USA.
²⁸ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁹ University of Texas Medical Branch, Galveston, Texas, USA.
³⁰ University of Texas at Austin, Austin, Texas, USA.
³¹ Arbutus Biopharma, Inc, Warminster, Pennsylvania, USA.
³² PTC Therapeutics, Inc, South Plainfield, New Jersey, USA.
³³ University of Connecticut School of Medicine, Farmington, Connecticut, USA.

PMID: 34111271
PMCID: PMC8280938
DOI: 10.1093/infdis/jiab305

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Matthew D Hall et al. J Infect Dis. 2021.

. 2021 Jul 15;224(Supplement_1):S1-S21.

doi: 10.1093/infdis/jiab305.

Authors

Affiliations

¹ National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
² Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
³ Pfizer Vaccine Research and Development, Pfizer, Pearl River, New York, USA.
⁴ University of Washington, Seattle, Washington, USA.
⁵ Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
⁶ The Rockefeller University, New York, New York, USA.
⁷ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁸ Evotec, Lyon, France.
⁹ University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Evrys Bio, Doylestown, Pennsylvania, USA.
¹¹ Gilead Sciences, Foster City, California, USA.
¹² Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
¹³ Vanderbilt University, Nashville, Tennessee, USA.
¹⁴ Scripps Research, Jupiter, Florida, USA.
¹⁵ University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁶ University of Alberta, Edmonton, Alberta, Canada.
¹⁷ University of Virginia, Charlottesville, Virginia, USA.
¹⁸ Merck & Co, Inc, Kenilworth, New Jersey, USA.
¹⁹ Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
²⁰ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
²¹ Purdue University, West Lafayette, Indiana, USA.
²² University of Alabama at Birmingham, Birmingham, Alabama, USA.
²³ 1910 Genetics, Inc, Cambridge, Massachusetts, USA.
²⁴ US Food and Drug Administration, Silver Spring, Maryland, USA.
²⁵ Emory University, Atlanta, Georgia, USA.
²⁶ Takeda California, Inc, San Diego, California, USA.
²⁷ University of Massachusetts Medical School, Worcester, Massachusetts, USA.
²⁸ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁹ University of Texas Medical Branch, Galveston, Texas, USA.
³⁰ University of Texas at Austin, Austin, Texas, USA.
³¹ Arbutus Biopharma, Inc, Warminster, Pennsylvania, USA.
³² PTC Therapeutics, Inc, South Plainfield, New Jersey, USA.
³³ University of Connecticut School of Medicine, Farmington, Connecticut, USA.

PMID: 34111271
PMCID: PMC8280938
DOI: 10.1093/infdis/jiab305

Abstract

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.

Keywords: SARS-CoV-2; antiviral therapeutics; emerging modalities; preclinical; proteases; viral replication machinery.

Published by Oxford University Press for the Infectious Diseases Society of America 2021.

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Figures

**Figure 1.**
Scheme showing the SARS-CoV-2 viral replication cycle and “druggable” events. The SARS-CoV-2 virion is composed of a capsid protein coat, with an internal core of the viral genetic material (RNA). 1. Viral entry. The SARS-CoV-2 virion in the extracellular space presents Spike (S) protein on the capsid surface. The S protein contains a number of host protease cleavage sites, as well as the receptor binding domain (RBD). Engagement of spike protein at the extracellular surface involves engagement of multiple host cell proteins including (but may not be limited to) cleavage of S by the protease furin (gene *FURIN*), binding of the S RBD to ACE2 (*ACE2*), engagement of a liberated S terminal peptide to neuropilin-1 (Nrp-1, *NRP1*), and cleavage of S by the serine protease TMPRSS2 (TMPRSS2). 2. Following endocytosis, the virion is uncoated, and the large positive-sense viral RNA translated into polypeptide chains. 3. Two viral proteases cleave the viral polypeptide chains to produce up to 29 mature protein products. These proteases are the main protease (Mpro) and the papain-like protease (PLpro). 4. Viral RNA replication follows, with the formation of a replication-transcription complex, incorporating the RNA-dependent RNA polymerase (RdRp). 5. The arising viral RNA (genetic material) is then packaged into capsid formed by viral protein including envelope (E), membrane (M), nucleocapsid (N) and aforementioned spike. Mature packaged virion is then trafficked via lysosomes, and 6. Virion is released via exocytosis. Schematic prepared by Kyle R. Brimacombe, NCATS. Abbreviations: ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

**Figure 2.**
Structures of nucleoside analogs for the treatment of COVID-19 and their metabolic activation. Abbreviations: COVID-19, coronavirus disease 2019; TBD, to be disclosed.

See this image and copyright information in PMC

References

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Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

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Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

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