PreprintCited by 154SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesAnimal Virus Infections Studies

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

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Boras, Britton, Jones, Rhys M., Anson, Brandon J., Arenson, Dan, Aschenbrenner, Lisa, Bakowski, Malina A., Beutler, Nathan, Binder, Joseph +41 more·2020·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

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Crossref · 10.1101/2020.09.12.293498

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  • Pfizer developed an Mpro inhibitor prodrug, PF-07304814, which is given intravenously and entered clinical trials in hospitalized patients with COVID-19 in 2020.

    “Pfizer has also developed an Mpro inhibitor prodrug, PF-07304814 (ref.203), which is given intravenously and which entered clinical trials in hospitalized patients with COVID-19 in 2020 (NCT04535167).”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [203]

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  1. Bakowski, M. A. et al. Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19. bioRxiv 2020.06.16.153403 (2020) doi:10.1101/2020.06.16.153403. · DOI

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Authors
Boras, B., Jones, R. M., Anson, B. J., Arenson, D., Aschenbrenner, L., Bakowski, M. A., Beutler, N., Binder, J., Chen, E., Eng, H., Hammond, H., Hammond, J., Haupt, R. E., Hoffman, R., Kadar, E. P., Kania, R., Kimoto, E., Kirkpatrick, M. G., Lanyon, L., Lendy, E. K., Lillis, J. R., Logue, J., Luthra, S. A., Ma, C., Mason, S. W., McGrath, M. E., Noell, S., Obach, R. S., O’Brien, M. N., O’Connor, R., Ogilvie, K., Owen, D., Pettersson, M., Reese, M. R., Rogers, T. F., Rossulek, M. I., Sathish, J. G., Shirai, N., Steppan, C., Ticehurst, M., Updyke, L. W., Weston, S., Zhu, Y., Wang, J., Chatterjee, A. K., Mesecar, A. D., Frieman, M. B., Anderson, A. S., & Allerton, C.
Affiliations
  • Pfizer (United States) (US)
  • Purdue University West Lafayette (US)
  • Scripps Research Institute (US)
  • University of Maryland, Baltimore (US)
  • Pfizer (United Kingdom) (GB)
  • University of Arizona (US)
Corresponding author
Jones, Rhys M.
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2020-09-13
OpenAlex
W3085670077
Cited by
154
References
63
Citations by year
2026: 1 · 2025: 3 · 2024: 7 · 2023: 9 · 2022: 24 · 2021: 89 · 2020: 21
Type
posted content
Language
en
Open access
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Pfizer
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
SARS-CoV-2, COVID-19 pandemic, main protease, Mpro inhibitors, phosphate prodrugs, antiviral activity, drug selectivity, ADME, drug safety, clinical candidates

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