An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6575; pp. 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: Journal Article
• Language: English
• Published: United States 24.12.2021
• 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
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abl4784

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.