Kaustav Khatua, Yugendar R Alugubelli, Kai S Yang, Veerabhadra R Vulupala, Lauren R Blankenship, Demonta Coleman, Sandeep Atla, Sankar P Chaki, Zhi Zachary Geng, Xinyu R Ma, Jing Xiao, Peng-Hsun Chen, Chia-Chuan D Cho, Shivangi Sharma, Erol C Vatansever, Yuying Ma, Ge Yu, Benjamin W Neuman, Shiqing Xu, Wenshe Ray Liu
The main protease (MPro ) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro 's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875...
March 28, 2024: Antiviral Research