An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease

Author:

Khatua KaustavORCID,Alugubelli Yugendar R.,Yang Kai S.,Vulupala Veerabhadra R.,Blankenship Lauren R.,Coleman Demonta D.,Atla Sandeep,Chaki Sankar P.ORCID,Geng Zhi Zachary,Ma Xinyu R.,Xiao Jing,Chen Peng-Hsun Chase,Cho Chia-Chuan Dean,Vatansever Erol C.,Ma Yuying,Yu Ge,Neuman Benjamin W.,Xu Shiqing,Liu Wenshe Ray

Abstract

ABSTRACTMain protease (MPro) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 Cα atom in an MProsubstrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the MProcatalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent MProinhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC50value in inhibiting SARS-CoV-2 from infecting ACE2+A549 cells and a selectivity index of 875. The crystallography analyses of MProbound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent MProinhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 MProas therapeutics for COVID-19.

Publisher

Cold Spring Harbor Laboratory

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