Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity.

Autor: Paulis A; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy., Onali A; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy., Vidalain PO; CIRI, Centre International de Recherche en Infectiologie, University Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon F-69007, France., Lotteau V; CIRI, Centre International de Recherche en Infectiologie, University Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon F-69007, France., Jaquemin C; CIRI, Centre International de Recherche en Infectiologie, University Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon F-69007, France., Corona A; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy., Distinto S; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy. Electronic address: s.distinto@unica.it., Delogu GL; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy., Tramontano E; Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy. Electronic address: tramon@unica.it.
Jazyk: angličtina
Zdroj: Virus research [Virus Res] 2024 Sep; Vol. 347, pp. 199432. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1016/j.virusres.2024.199432
Abstrakt: The Stimulator of Interferon Genes (STING) is involved in cytosolic DNA sensing and type I Interferons (IFN-I) induction. Aiming to identify new STING agonists with antiviral activity and given the known biological activity of benzothiazole and benzimidazole derivatives, a series of benzofuran derivatives were tested for their ability to act as STING agonists, induce IFN-I and inhibit viral replication. Compounds were firstly evaluated in a gene reporter assay measuring luciferase activity driven by the human IFN-β promoter in cells expressing exogenous STING (HEK293T). Seven of them were able to induce IFN-β transcription while no induction of the IFN promoter was observed in the presence of a mutated and inactive STING, showing specific protein-ligand interaction. Docking studies were performed to predict their putative binding mode. The best hit compounds were then tested on human coronavirus 229E replication in BEAS-2B and MRC-5 cells and three derivatives showed EC 50 values in the μM range. Such compounds were also tested on SARS-CoV-2 replication in BEAS-2B cells and in Calu-3 showing they can inhibit SARS-CoV-2 replication at nanomolar concentrations. To further confirm their IFN-dependent antiviral activity, compounds were tested to verify their effect on phospho-IRF3 nuclear localization, that was found to be induced by benzofuran derivatives, and SARS-CoV-2 replication in Vero E6 cells, lacking IFN production, founding them to be inactive. In conclusion, we identified benzofurans as STING-dependent immunostimulatory compounds and host-targeting inhibitors of coronaviruses representing a novel chemical scaffold for the development of broad-spectrum antivirals.
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 B.V. All rights reserved.)
Databáze: MEDLINE
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