The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target.

Autor: Rona G; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA.; Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA., Zeke A; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA.; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, HU-1117, Hungary., Miwatani-Minter B; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA., de Vries M; Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA., Kaur R; Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA., Schinlever A; Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA., Garcia SF; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA., Goldberg HV; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA., Wang H; Department of Pharmacology and University of Washington, Seattle, WA, 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA., Hinds TR; Department of Pharmacology and University of Washington, Seattle, WA, 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA., Bailly F; Univ Lille, INSERM, CHU Lille, UMR-S 1172, Lille Neuroscience and Cognition Research Center, F-59000, Lille, France., Zheng N; Department of Pharmacology and University of Washington, Seattle, WA, 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA., Cotelle P; Univ Lille, INSERM, CHU Lille, UMR-S 1172, Lille Neuroscience and Cognition Research Center, F-59000, Lille, France.; ENSCL-Centrale Lille, CS 90108, F-59652, Villeneuve d'Ascq, France., Desmaële D; Institut Galien, Université Paris-Saclay, 92296, Châtenay-Malabry, France., Landau NR; Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA., Dittmann M; Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA. meike.dittmann@nyumc.org., Pagano M; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, 10016, USA. michele.pagano@nyumc.org.; Laura and Isaac Perlmutter NYU Cancer Center and NYU Grossman School of Medicine, New York, NY, 10016, USA. michele.pagano@nyumc.org.; Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA. michele.pagano@nyumc.org.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2022 Feb; Vol. 29 (2), pp. 285-292. Date of Electronic Publication: 2021 Dec 03.
DOI: 10.1038/s41418-021-00900-1
Abstrakt: The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir's potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.
(© 2021. The Author(s).)
Databáze: MEDLINE
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