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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

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

2025-11-03 microbiology
10.1101/2025.10.30.685646 bioRxiv
Show 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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