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

We have witnessed three coronavirus (CoV) outbreaks in
the past
two decades, including the COVID-19 pandemic caused by SARS-CoV-2.
Main protease (MPro), 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 MPro. Among them, MPD2 was demonstrated to
effectively reduce MPro protein levels in 293T cells, relying
on a time-dependent, CRBN-mediated, and proteasome-driven mechanism.
Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells.
MPD2 also displayed potent antiviral activity against various SARS-CoV-2
strains and exhibited enhanced potency against nirmatrelvir-resistant
viruses. Overall, this proof-of-concept study highlights the potential
of targeted protein degradation of MPro as an innovative
approach for developing antivirals that could fight against drug-resistant
viral variants.