Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2.

ABSTRACT: Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL^pro ) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2?b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL^pro . Moreover, we report the discovery of isoindolines as a new class of potent PL^pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL^pro are valuable starting points for the development of new pan-coronaviral inhibitors.

SUBMITTER: Welker A 

PROVIDER: S-EPMC7894572 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature