Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus.

ABSTRACT:

Background

Effective antiviral therapy is lacking for most viral infections, and when available, is frequently compromised by the selection of resistance. Targeted protein degraders could provide an avenue to more effective antivirals, able to overcome the selection of resistance. The aim of this study was to determine whether adaptation of SARS-CoV-2 main protease (Mpro, also described as chymotrypsin-like protease (3CL^pro) or non-structural protein 5 (Nsp5)) inhibitors into degraders leads to increased antiviral activity, including activity against resistant virus.

Methods

We adapted the clinically approved Mpro inhibitor nirmatrelvir into a panel of degraders. Size-matched non-degrading controls were also synthesised to discriminate degradation activity from in

SUBMITTER: Pan B 

PROVIDER: S-EPMC12033352 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature