Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease.

ABSTRACT: We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M^Pro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M^Pro. Among them, MPD2 was demonstrated to effectively reduce M^Pro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M^Pro protein levels in SARS-CoV-2-infected A54

SUBMITTER: Alugubelli YR 

PROVIDER: S-EPMC11056980 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature