Abstract
3CL protease (3CL(pro)), a key enzyme of SARS-CoV-2 replication, is one of the most selective targets of antivirals, as no homologous protease has been recognized in the human body. As proteolysis-targeting chimeras (PROTACs) are superior to traditional inhibitors, based on the reported cereblon (CRBN) ligands thalidomide and lenalidomide, 3CL(pro) ligands of peptidomimetic inhibitors, and suitable linkers, we aimed to develop novel PROTACs that may trigger efficient intracellular 3CL(pro) degradation through a balance of hydrophilicity and lipophilicity. In brief, we designed and synthesized 5 PROTAC molecules. The 3CL(pro) degradation efficiency of the PROTACs was assayed in stable SARS-CoV-2 3CL(pro) expression HEK293 cell models and evaluated by Western blot. All compounds showed prominent 3CL(pro) degradation activity with tolerable HEK293 cytotoxicity. The most prominent PROTAC compounds, 15 and 16, have DC(50) values of approximately 1 µM, and D(max) of 89.3% and 75% respectively, indicating good potential for further application.