Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19
Open accessAbstract
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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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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- 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.
- ORCID
- Boras, Britton
- Jones, Rhys M.
- Anson, Brandon J.
- Aschenbrenner, Lisa
- Bakowski, Malina A.
- Beutler, Nathan
- Chen, Emily
- Eng, Heather
- Hammond, Holly
- Hammond, Jennifer
- Haupt, Robert E.
- Hoffman, Robert
- Kadar, Eugene P.
- Kimoto, Emi
- Kirkpatrick, Melanie G.
- Lendy, Emma K.
- Logue, James
- Luthra, Suman A.
- Ma, Chunlong
- Mason, Stephen W.
- McGrath, Marisa E.
- Noell, Stephen
- Obach, R. Scott
- O’Brien, Matthew N.
- Ogilvie, Kevin
- Owen, Dafydd
- Pettersson, Martin
- Reese, Matthew R
- Rogers, Thomas F.
- Rossulek, Michelle I.
- Sathish, Jean G.
- Shirai, Norimitsu
- Steppan, Claire
- Ticehurst, Martyn
- Weston, Stuart
- Zhu, Yuao
- Wang, Jun
- Chatterjee, Arnab K.
- Mesecar, Andrew D.
- Frieman, Matthew B.
- Anderson, Annaliesa S.
- Allerton, Charlotte
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-09-13
- PMC
- PMC7491518
- 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
- green
- doi.org
- 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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