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bioRxiv · 10.1101/2025.10.30.685646

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.
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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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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. In vitro Characterization of Peptidomimetic Proteolysis Targeting Chimera (PROTAC) as a Degrader of 3-Chymotrypsin-Like Protease (Mpro/3CLpro) against SARS-CoV-2. https://doi.org/10.1101/2025.10.30.685646

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