The development of Coronavirus 3C-Like protease (3CL^pro) inhibitors from 2010 to 2020

Highlights

• This article provides a comprehensive overview of the coronavirus 3CL^pro inhibitors developed from 2010 to 2020.

• The SARs, binding modes of peptidomimetic and nonpeptidic inhibitors are comprehensively analysed.

• As anti-coronavirus candidates, reversible covalent PROTACs for 3CL^pro could induce the intracellular degradation of 3CL^pro.

Abstract

This review fully describes the coronavirus 3CL^pro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CL^pro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CL^pro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1’, S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CL^pro inhibitors, 3CL^pro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.