Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity

• DOI: 10.1016/j.ejmech.2024.116202
• Publication Date: 2024-02-06T18:53:16Z
• Authors: Jenny Desantis; Alessandro Bazzacco; Michela Eleuteri; Sara Tuci; Elisa Bianconi; Antonio Macchiarulo; Beatrice Mercorelli; Arianna Loregian; Laura Goracci
• Keywords: Broad spectrum

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in field antiviral drug discovery is still infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum activity against coronaviruses. Here, report design, synthesis, characterization a novel series INM-based that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel was also enlarged by varying linker moiety. resulted very susceptible this modification, particularly for hijacking VHL as ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 infected human lung cells. Interestingly, assays both uninfected virus-infected cells most promising emerged so far (PROTACs 5 demonstrated INM-PROTACs do not degrade PGES-2 protein, initially hypothesized, but induce concentration-dependent SARS-CoV-2 main protease (Mpro) Mpro-transfected SARS-CoV-2-infected Importantly, thanks target degradation, exhibited considerable enhancement respect indomethacin, EC50 values low-micromolar/nanomolar range. Finally, kinetic solubility well metabolic chemical stability were measured 6. Altogether, identification first class Mpro degraders demonstrating represents significant advance development effective, anti-coronavirus strategies.