An oral SARS-CoV-2 M pro inhibitor clinical candidate 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...

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Published in:	Science (American Association for the Advancement of Science) 2021-12, Vol.374 (6575), p.1586-1593
Main Authors:	Owen, Dafydd R, Allerton, Charlotte M N, Anderson, Annaliesa S, Aschenbrenner, Lisa, Avery, Melissa, Berritt, Simon, Boras, Britton, Cardin, Rhonda D, Carlo, Anthony, Coffman, Karen J, Dantonio, Alyssa, Di, Li, Eng, Heather, Ferre, RoseAnn, Gajiwala, Ketan S, Gibson, Scott A, Greasley, Samantha E, Hurst, Brett L, Kadar, Eugene P, Kalgutkar, Amit S, Lee, Jack C, Lee, Jisun, Liu, Wei, Mason, Stephen W, Noell, Stephen, Novak, Jonathan J, Obach, R Scott, Ogilvie, Kevin, Patel, Nandini C, Pettersson, Martin, Rai, Devendra K, Reese, Matthew R, Sammons, Matthew F, Sathish, Jean G, Singh, Ravi Shankar P, Steppan, Claire M, Stewart, Al E, Tuttle, Jamison B, Updyke, Lawrence, Verhoest, Patrick R, Wei, Liuqing, Yang, Qingyi, Zhu, Yuao
Format:	Article
Language:	eng
Subjects:	Administration, Oral Animals Clinical Trials, Phase I as Topic Coronavirus - drug effects COVID-19 - drug therapy COVID-19 - virology Disease Models, Animal Drug Therapy, Combination Humans Lactams - administration & dosage Lactams - pharmacokinetics Lactams - pharmacology Lactams - therapeutic use Leucine - administration & dosage Leucine - pharmacokinetics Leucine - pharmacology Leucine - therapeutic use Mice Mice, Inbred BALB C Microbial Sensitivity Tests Nitriles - administration & dosage Nitriles - pharmacokinetics Nitriles - pharmacology Nitriles - therapeutic use Proline - administration & dosage Proline - pharmacokinetics Proline - pharmacology Proline - therapeutic use Randomized Controlled Trials as Topic Ritonavir - administration & dosage Ritonavir - therapeutic use SARS-CoV-2 - drug effects SARS-CoV-2 - physiology Viral Protease Inhibitors - administration & dosage Viral Protease Inhibitors - pharmacokinetics Viral Protease Inhibitors - pharmacology Viral Protease Inhibitors - therapeutic use Virus Replication - drug effects
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Summary:	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.
ISSN:	0036-8075 1095-9203