A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.

Automated summary

The SARS-CoV-2 pandemic is causing an unprecedented global health emergency. The FDA has granted emergency use authorization to nirmatrelvir for treating infected patients. The study investigated nirmatrelvir analogs with different warheads and their inhibitory activities, finding that hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting their potential use for treating coronavirus infections.