Withaferin A, a polyfunctional pharmacophore that includes covalent engagement of IPO5, is an inhibitor of influenza A replication.

Autor: Patouret R; Department of Organic Chemistry, Faculty of Science, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland., Barluenga S; Department of Organic Chemistry, Faculty of Science, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland., Winssinger N; Department of Organic Chemistry, Faculty of Science, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland. Electronic address: nicolas.winssinger@unige.ch.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2022 Sep 01; Vol. 69, pp. 116883. Date of Electronic Publication: 2022 Jun 18.
DOI: 10.1016/j.bmc.2022.116883
Abstrakt: Withaferin A, a natural steroidal lactone found in the extracts of Withania somnifera, is used extensively in traditional medicine and part of an ancient remedy in ayurvedic medicine. Prior investigations into its mode of action have shown withaferin to be a polyfunctional pharmacophore with the covalent engagement of a multitude of therapeutic targets. Herein, we report that withaferin A is also a covalent inhibitor of IPO5, an importin that translocates cargos from the cytosol to the nucleus. We show that withaferin inhibits influenza A replication in epithelial cells (A549). Using a panel of inhibitors that selectively recapitulate part of withaferin A's pharmacological profile (goyazensolide, withaferin A derivatives, FiVe1, and bardoxolone methyl), we show that IPO5 inhibition contributes to the influenza replication inhibition but is not essential for the observed activity of withaferin A. We show that bardoxolone methyl, a semisynthetic triterpenoid in clinical development to treat chronic kidney disease and that shares some of the pharmacological profile of withaferin, also inhibits influenza A replication effectively. The inhibitory activity against influenza A replication should stimulate further studies to repurpose this therapeutic.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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