An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19
By D. Owen, C. Allerton, A. Anderson, L. Aschenbrenner, M. Avery, S. Berritt, B. Boras, R. Cardin, A. Carlo, K. Coffman and 32 more. Science, 2021
1,698 citations recorded by the source corpus.
Description 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 PF-07321332 is an orally active, small-molecule inhibitor of the SARS-CoV-2 main protease that is in clinical trials for the treatment of COVID-19. The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Subfields: Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/136e519843a3af09023ff2076672623cb0b9a113
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Citations in the corpus
- Computational approaches streamlining drug discovery (2023, methodology): “The best compound in this work had good in vitro ADMET properties, with an affinity of 38 nM and a cell-based antiviral potency of 77 nM, which are comparable to clinically used PF-07321332 (nirmatrelvir) 65 .”