A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir
Subramanyam Vankadara, Monique Danielle Dawson, Jia Yi Fong, Qin Yao Oh, Qi An Ang, Bo Liu, Hong Chang, Judice LY Koh, Xiaoying Koh, Qian Tan, Joma Joy, C. S. Brian Chia
Abstract
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.