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 (M ^Pro ) is a highly conserved and essential protease that plays key roles in viral replication and pathogenesis among various CoVs, representing one of the most attractive drug targets for antiviral drug development. Traditional antiviral drug development strategies focus on the pursuit of high-affinity binding inhibitors against M ^Pro . However, this approach often suffers from issues such as toxicity, drug resistance, and a lack of broad-spectrum efficacy. Targeted protein degradation represents a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. Here we leverage the proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M ^Pro . Our previously developed M ^Pro inhibitors MPI8 and MPI29 were used as M ^Pro ligands to conjugate a CRBN E3 ligand, leading to compounds that can both inhibit and degrade SARS-CoV-2 M ^Pro . Among them, MDP2 was demonstrated to effectively reduce M ^Pro protein levels in 293T cells (DC ₅₀ = 296 nM), 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 A549-ACE2 cells, concurrently demonstrating potent anti-SARS-CoV-2 activity (EC ₅₀ = 492 nM). This proof-of-concept study highlights the potential of PROTAC-mediated targeted protein degradation of M ^Pro as an innovative and promising approach for COVID-19 drug discovery.