دورية أكاديمية
Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity.
| العنوان: | Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity. |
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| المؤلفون: | Desantis J; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Italy., Bazzacco A; Department of Molecular Medicine, University of Padua, Padua, Italy., Eleuteri M; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Italy., Tuci S; Department of Molecular Medicine, University of Padua, Padua, Italy., Bianconi E; Department of Pharmaceutical Science, University of Perugia, Italy., Macchiarulo A; Department of Pharmaceutical Science, University of Perugia, Italy., Mercorelli B; Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: beatrice.mercorelli@unipd.it., Loregian A; Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: arianna.loregian@unipd.it., Goracci L; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Italy. Electronic address: laura.goracci@unipg.it. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2024 Mar 15; Vol. 268, pp. 116202. Date of Electronic Publication: 2024 Feb 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Proteolysis Targeting Chimera* , COVID-19* , Coronavirus 3C Proteases*, Humans ; Proteolysis ; SARS-CoV-2/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Antiviral Agents/pharmacology |
| مستخلص: | To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related to oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in the field of antiviral drug discovery is still in its infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum antiviral activity against coronaviruses. Here, we report the design, synthesis, and characterization of a novel series of INM-based PROTACs that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel of INM-based PROTACs was also enlarged by varying the linker moiety. The antiviral activity resulted very susceptible to this modification, particularly for PROTACs hijacking VHL as E3 ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 activity in infected human lung cells. Interestingly, degradation assays in both uninfected and virus-infected cells with the most promising PROTACs emerged so far (PROTACs 5 and 6) demonstrated that INM-PROTACs do not degrade human PGES-2 protein, as initially hypothesized, but induce the concentration-dependent degradation of SARS-CoV-2 main protease (M pro ) both in M pro -transfected and in SARS-CoV-2-infected cells. Importantly, thanks to the target degradation, INM-PROTACs exhibited a considerable enhancement in antiviral activity with respect to indomethacin, with EC Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Antiviral; Main protease (M(pro)); PROTAC; SARS-CoV-2; Targeted protein degradation |
| المشرفين على المادة: | EC 3.4.22.- (3C-like proteinase, SARS-CoV-2) 0 (Proteolysis Targeting Chimera) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (Antiviral Agents) EC 3.4.22.28 (Coronavirus 3C Proteases) |
| تواريخ الأحداث: | Date Created: 20240223 Date Completed: 20240318 Latest Revision: 20240318 |
| رمز التحديث: | 20240318 |
| DOI: | 10.1016/j.ejmech.2024.116202 |
| PMID: | 38394929 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2024.116202 |