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Indomethacin-based PROTACs as pan-coronavirus antiviral agents.
Desantis, Jenny; Mercorelli, Beatrice; Celegato, Marta; Croci, Federico; Bazzacco, Alessandro; Baroni, Massimo; Siragusa, Lydia; Cruciani, Gabriele; Loregian, Arianna; Goracci, Laura.
  • Desantis J; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Mercorelli B; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Celegato M; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Croci F; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Italy.
  • Bazzacco A; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Baroni M; Molecular Discovery Ltd., Centennial Park, Borehamwood, Hertfordshire, United Kingdom.
  • Siragusa L; Molecular Horizon Srl, Bettona, 06084, Italy.
  • Cruciani G; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Italy.
  • 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.
Eur J Med Chem ; 226: 113814, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1385490
ABSTRACT
Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein. Although INM does not potently inhibit SARS-CoV-2 replication in infected Vero E6 cells, here we have explored for the first time the application of the Proteolysis Targeting Chimeras (PROTACs) technology in order to develop more potent INM-derived PROTACs with anti-CoV activity. In this study, we report the design, synthesis, and biological evaluation of a series of INM-based PROTACs endowed with antiviral activity against a panel of human CoVs, including different SARS-CoV-2 strains. Two PROTACs showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies support human PGES-2 as a potential target of INM-based antiviral PROTACs, thus paving the way toward the development of host-directed anti-CoVs strategies. To the best of our knowledge, these PROTACs represent the first-in-class INM-based PROTACs with antiviral activity and also the first example of the application of PROTACs to develop pan-coronavirus agents.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Indomethacin / SARS-CoV-2 / COVID-19 Type of study: Experimental Studies Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2021 Document Type: Article Affiliation country: J.ejmech.2021.113814

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Indomethacin / SARS-CoV-2 / COVID-19 Type of study: Experimental Studies Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2021 Document Type: Article Affiliation country: J.ejmech.2021.113814