Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M^pro and cathepsin L.

ABSTRACT: The main protease (M^pro) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 M^pro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently discovered several M^pro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of M^pro in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent M^pro inhibitors in vitro. The struct

SUBMITTER: Sacco MD 

PROVIDER: S-EPMC7402059 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature