Structural highlights
Publication Abstract from PubMed
SARS-CoV-2 main protease (M(pro)) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M(pro) mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M(pro) inhibitors. In this study, we explored several reactive warheads in the design of M(pro) inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M(pro) inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC(50) values of 2.92 and 6.47 muM, respectively. X-ray crystal structures of M(pro) with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M(pro) inhibitors with diverse reactive warheads collectively represent promising candidates for further development.
Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.,Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J Eur J Med Chem. 2023 Nov 5;259:115667. doi: 10.1016/j.ejmech.2023.115667. Epub , 2023 Jul 19. PMID:37482021[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J. Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors. Eur J Med Chem. 2023 Jul 19;259:115667. PMID:37482021 doi:10.1016/j.ejmech.2023.115667
