bioRxivMicrobiologyPreprint
In vitro Characterization of Peptidomimetic Proteolysis Targeting Chimera (PROTAC) as a Degrader of 3-Chymotrypsin-Like Protease (Mpro/3CLpro) against SARS-CoV-2
Mirko Giuseppe LiturriiD, Annalisa BergnaiD, Alessia LaiiD, Carla Della VenturaiD, Arianna GabrieliiD, Ioana Seravalli, Simone Ciofi‐BaffoniiD, Elena LenciiD, Andrea TrabocchiiD, Stefano RusconiiD
Abstract
The SARS-CoV-2 main protease (3CLpro) is a key target for antiviral development. We investigated FT235, a peptidomimetic PROTAC linking a GC-376 warhead to pomalidomide for targeted degradation. FT235 bound 3CLpro, inhibiting activity (IC50 = 21.2 {micro}M), and reducing protease levels in cells. In vitro data showed no cytotoxicity up to 100 {micro}M and variant-dependent antiviral activity, with increased potency in the presence of a P-gp inhibitor. These results support PROTAC-based antivirals as promising therapeutic candidates.
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