Application of the PROTAC-based approach to trigger proteolysis of the Coxsackievirus B3 main protease

The conservation of the main protease in viral genomes, combined with the absence of a homologous protease in humans, makes this enzyme family an ideal target for developing broad spectrum antiviral drugs with minimized host toxicity. GC-376, a peptidomimetic 3CL protease inhibitor, has shown significant efficacy against coronaviruses. Recently, we have shown that a GC-376-based PROTAC specifically targets and induces the proteasome mediated degradation of the dimeric SARS CoV-2 3CLPro protein. Expanding this approach, we investigated the application of the GC-376 PROTAC to the 3CPro protease of enteroviruses, characterizing its interaction with Coxsackievirus B3 (CVB3) 3CPro through X-ray crystallography, NMR (Nuclear Magnetic Resonance) and biochemical techniques.