An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19
Open accessPublished version of a preprint
Abstract
Path to another drug against COVID-19: The rapid development of vaccines has been crucial in battling the ongoing COVID-19 pandemic. However, access challenges remain, breakthrough infections occur, and emerging variants present increased risk. Developing antiviral therapeutics is therefore a high priority for the treatment of COVID-19. Some drug candidates in clinical trials act against the viral RNA-dependent RNA polymerase, but there are other viral enzymes that have been considered good targets for inhibition by drugs. Owen et al . report the discovery and characterization of a drug against the main protease involved in the cleavage of polyproteins involved in viral replication. The drug, PF-07321332, can be administered orally, has good selectivity and safety profiles, and protects against infection in a mouse model. In a phase 1 clinical trial, the drug reached concentrations expected to inhibit the virus based on in vitro studies. It also inhibited other coronaviruses, including severe acute respiratory syndrome coronavirus 1 and Middle East respiratory syndrome coronavirus, and could be in the armory against future viral threats. —VV
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Nirmatrelvir has in vivo efficacy in a mouse-adapted SARS-CoV-2 (MA10) model.
“The in vivo efficacy of nirmatrelvir was demonstrated in a mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA10) model.”
From Advances in covalent drug discovery (2022) · cites this paper as [103]
The nitrile group of nirmatrelvir reacts with Cys145 of SARS-CoV-2 main protease to form a covalent thioimidate adduct.
“The nitrile group of nirmatrelvir (shown in green) reacts with Cys145 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (shown in light blue) to form a covalent thioimidate adduct.”
From Advances in covalent drug discovery (2022) · cites this paper as [103]
PF-00835231 potently inhibits SARS-CoV-2 main protease in a FRET-based activity assay.
“PF-00835231, which demonstrated potent SARS-CoV-2 Mpro inhibition in an activity assay based on fluorescence resonance energy transfer (FRET)”
From Advances in covalent drug discovery (2022) · cites this paper as [103]
Replacing the α-hydroxymethylketone moiety of PF-00835231 with a nitrile group improved its oral bioavailability.
“the oral bioavailability of PF-00835231 was improved by replacing the α-hydroxymethylketone moiety with a nitrile group, which can also act as an electrophile103.”
From Advances in covalent drug discovery (2022) · cites this paper as [103]
Nirmatrelvir is a highly potent reversible covalent inhibitor of SARS-CoV-2.
“PF-07321332, named nirmatrelvir (Fig. 4 and Table 1), which is a highly potent SARS-CoV-2 reversible covalent inhibitor”
From Advances in covalent drug discovery (2022) · cites this paper as [103]
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- Authors
- Owen, D. R., Allerton, C. M. N., Anderson, A. S., Aschenbrenner, L., Avery, M., Berritt, S., Boras, B., Cardin, R. D., Carlo, A., Coffman, K. J., Dantonio, A., Di, L., Eng, H., Ferre, R., Gajiwala, K. S., Gibson, S. A., Greasley, S. E., Hurst, B. L., Kadar, E. P., Kalgutkar, A. S., Lee, J. C., Lee, J., Liu, W., Mason, S. W., Noell, S., Novak, J. J., Obach, R. S., Ogilvie, K., Patel, N. C., Pettersson, M., Rai, D. K., Reese, M. R., Sammons, M. F., Sathish, J. G., Singh, R. S. P., Steppan, C. M., Stewart, A. E., Tuttle, J. B., Updyke, L., Verhoest, P. R., Wei, L., Yang, Q., & Zhu, Y.
- Affiliations
- Pfizer (United States) (US)
- Pfizer Worldwide Research, Development & Medical, La Jolla, CA 92121, USA.
- Utah State University (US)
- Corresponding author
- Owen, Dafydd R.
- ORCID
- Owen, Dafydd R.
- Allerton, Charlotte M. N.
- Anderson, Annaliesa S.
- Aschenbrenner, Lisa
- Berritt, Simon
- Boras, Britton
- Cardin, Rhonda D.
- Coffman, Karen J.
- Dantonio, Alyssa
- Di, Li
- Eng, Heather
- Ferre, RoseAnn
- Gajiwala, Ketan S.
- Greasley, Samantha E.
- Hurst, Brett L.
- Kadar, Eugene P.
- Kalgutkar, Amit S.
- Lee, Jisun
- Liu, Wei
- Mason, Stephen W.
- Noell, Stephen
- Novak, Jonathan J.
- Obach, R. Scott
- Ogilvie, Kevin
- Patel, Nandini C.
- Pettersson, Martin
- Reese, Matthew R.
- Sammons, Matthew F.
- Sathish, Jean G.
- Singh, Ravi Shankar P.
- Steppan, Claire M.
- Tuttle, Jamison B.
- Wei, Liuqing
- Yang, Qingyi
- Zhu, Yuao
- Venue
- Science
- Published
- 2021-12-24
- Volume
- 374
- Issue
- 6575
- Pages
- 1586-1593
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3189646261
- Cited by
- 2,033
- References
- 62
- Citations by year
- 2026: 265 · 2025: 322 · 2024: 427 · 2023: 482 · 2022: 508 · 2021: 27 · 2020: 1
- FWCI
- 117.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, Contract No. DE-AC02-06CH11357., AC02‐06CH11357, 06CH11357, No. DE-AC02-06CH11357, DE-AC02-)
- Pfizer
- Industrial Macromolecular Crystallography Association Collaborative Access Team (DE-AC02-06CH11357)
- Office of Science (Contract No. DE-AC02-06CH11357, AC02‐06CH11357, DE-AC02, No. DE-AC02-06CH11357., 06CH11357, DE-AC02-06CH11357)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, No. DE-AC02-06CH11357, 06CH11357, Contract No. DE-AC02-06CH11357.)
- 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, oral antivirals, coronavirus replication, SARS-CoV-1, MERS-CoV, antiviral drug discovery
- MeSH terms
- Viral Protease Inhibitors, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Administration, Oral, Animals, Disease Models, Animal, Drug Therapy, Combination, Humans, Lactams, Leucine, Mice, Inbred BALB C, Microbial Sensitivity Tests, Nitriles, Proline, Virus Replication, Randomized Controlled Trials as Topic, Clinical Trials, Phase I as Topic, Coronavirus, Ritonavir, Mice
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