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

2025 · doi:10.1101/2025.10.30.685646
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This study characterized FT235, a peptidomimetic PROTAC, which inhibited SARS-CoV-2 3CLpro activity and reduced its cellular levels, showing no cytotoxicity and variant-dependent antiviral effects.

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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 (IC 50 = 21.2 µM), and reducing protease levels in cells. In vitro data showed no cytotoxicity up to 100 µM 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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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 µM), and reducing protease levels in cells. In vitro data showed no cytotoxicity up to 100 µM 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. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

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last seen: 2026-05-20T01:45:00.602351+00:00