Reversible and irreversible inhibitors of coronavirus Nsp15 endoribonuclease.

Autor:	Chen J; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada., Farraj RA; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada., Limonta D; Department of Cell Biology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, California, USA., Tabatabaei Dakhili SA; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada., Kerek EM; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada., Bhattacharya A; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada., Reformat FM; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada., Mabrouk OM; Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada., Brigant B; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway., Pfeifer TA; High Throughput Biology Facility, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada., McDermott MT; Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada., Ussher JR; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada., Hobman TC; Department of Cell Biology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada., Glover JNM; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada., Hubbard BP; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address: basil.hubbard@utoronto.ca.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Nov; Vol. 299 (11), pp. 105341. Date of Electronic Publication: 2023 Oct 11.
DOI:	10.1016/j.jbc.2023.105341
Abstrakt:	The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less-explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is an irreversible inhibitor that might act via covalent modification of Cys residues within Nsp15. Moreover, we demonstrate that three of these inhibitors (hexachlorophene, IPA-3, and CID5675221) block severe acute respiratory syndrome coronavirus 2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors and pinpoints lead compounds for further development against coronavirus disease 2019 and related coronavirus infections. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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