Tricarbonyl Rhenium-Based PROTACs Degrade the SARS-CoV-2 Mpro Protease

Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) offers advantages over occupancy-based inhibitors but faces challenges, including ligand discovery and cellular permeability. To address these limitations, we developed Re2, a metallo-PROTAC integrating a covalent rhenium(I) complex warhead targeting SARS-CoV-2 main protease (Mpro) Cys145 with the cereblon E3 ligase ligand pomalidomide. Re2 induced effective intracellular Mpro degradation at 100 nM within 72 h, which is significantly below its parent complex's enzymatic inhibition concentration. In vitro and ex vivo studies confirmed covalent Mpro binding and ubiquitin-proteasome system-dependent degradation. Crucially, Re2 exhibited three- to fourfold higher cellular uptake and greater intracellular accumulation than its demetallated organic counterpart, demonstrating that metalation overcomes intrinsic PROTAC permeability barriers. This work establishes metallo-PROTACs, exploiting the tunable coordination chemistry of metal complexes for enhanced target engagement and cellular delivery, as a potent strategy for designing high-potent PROTACs.