The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic since its outbreak in December 2019. As of March 2022, COVID-19 continues to pose serious threats to global health, with more than 458 million confirmed cases and 6 million deaths. Despite wide availability of vaccines with proven protection, safe and effective treatment of COVID-19 is urgently needed to curtail the current pandemic and to combat future COVID pandemics or endemics. SARS-CoV-2 Mpro (or 3CLpro), a highly conserved cysteine protease among coronaviruses with no known human analogues, is responsible for proteolytic processing events essential for viral assembly and maturation. Given the critical role of SARS-CoV-2 Mpro in viral replication and the expected lack of resistance challenges conferred by spike protein variant mutations, covalent inhibition of SARS-CoV-2 Mpro represents an attractive approach for development of small-molecule antiviral therapy to treat COVID-19. By screening a panel of electrophilic warheads, we found a chemically stable one that could form an irreversible bond with the catalytic cysteine of SARS-CoV-2 Mpro. Installation of such warhead on various peptidomimetic scaffolds led to potent covalent inhibitors with excellent inhibitory activity against SARS-CoV-2 Mpro. The most potent inhibitor, 4CN53, in our series afforded nearly 10-fold more potent inhibition against SARS-CoV-2 Mpro in vitro than Nirmatrelvir (PF-07321332), the first oral antiviral with FDA emergency use approval for treating COVID-19 via SARS-CoV-2 Mpro inhibition. Furthermore, 4CN53 exhibited no observable cytotoxicity in Vero E6 cells at up to 100 uM. Evaluation of antiviral activity of 4CN53 in both cell and mouse models is being undertaken, which would validate 4CN53 or its derivatives as new therapeutic candidates for the treatment of COVID-19.

Discovery of novel covalent inhibitors of SARS-CoV-2 Mpro as anti-COVID therapeutics

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.