Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M^Pro inhibitors with potent in vivo efficacy.

ABSTRACT: The main protease (M^Pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M^Pro inhibition >1000-fold by engaging additional M^Pro subsites and using a latent electrophile to engage Cys¹⁴⁵. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for AVI-4773, a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for AVI-4773. AVI-4516 shows minimal inhi

SUBMITTER: Detomasi TC 

PROVIDER: S-EPMC12017303 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature