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In vitro Characterization of Peptidomimetic Proteolysis Targeting Chimera (PROTAC) as a Degrader of 3-Chymotrypsin-Like Protease (Mpro/3CLpro) against SARS-CoV-2

Created on 04 Nov 2025

Authors

Liturri, M. G., Bergna, A., Lai, A., Della Ventura, C., Gabrieli, A., Seravalli, I., Ciofi-Baffoni, S., Lenci, E., Trabocchi, A., Rusconi, S.

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 uM), and reducing protease levels in cells. In vitro data showed no cytotoxicity up to 100 uM 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Nov 2025.

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