Products Cited in Publications Worldwide Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors

Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors

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

DOI:

Abstract

The main (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural critical for viral replication and pathogenesis. Its function relies on three active site pockets for substrate recognition and a catalytic for enzymatic activity. To develop potential SARS-CoV-2 , we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic . 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. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.

Keywords

COVID-19 ; SARS-CoV-2 ; Main protease ; Azapeptide ; Covalent inhibitor

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