دورية أكاديمية
أعرض في EDS

Interfering with nucleotide excision by the coronavirus 3'-to-5' exoribonuclease.

التفاصيل البيبلوغرافية
العنوان: Interfering with nucleotide excision by the coronavirus 3'-to-5' exoribonuclease.
المؤلفون: Chinthapatla R; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Sotoudegan M; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Srivastava P; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Anderson TK; Department of Biochemistry and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA., Moustafa IM; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA., Passow KT; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Kennelly SA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Moorthy R; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Dulin D; Department of Physics and Astronomy, and LaserLaB Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Junior Research Group 2, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Cauerstr. 3, 91058 Erlangen, Germany., Feng JY; Gilead Sciences, Inc, Foster City, CA 94404, USA., Harki DA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Kirchdoerfer RN; Department of Biochemistry and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA., Cameron CE; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Arnold JJ; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
المصدر: Nucleic acids research [Nucleic Acids Res] 2023 Jan 11; Vol. 51 (1), pp. 315-336.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: Antiviral Agents*/pharmacology , Ribonucleotides*/chemistry , COVID-19 Drug Treatment*, Humans ; Exoribonucleases/metabolism ; RNA, Viral/genetics ; RNA, Viral/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/metabolism ; Virus Replication/genetics ; Drug Design
مستخلص: Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3'-to-5' proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3'-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3'-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.
(© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: R01 AI158463 United States AI NIAID NIH HHS; R01 AI161841 United States AI NIAID NIH HHS; P01 CA234228 United States CA NCI NIH HHS; R01 GM110129 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Antiviral Agents)
EC 3.1.- (Exoribonucleases)
0 (Ribonucleotides)
0 (RNA, Viral)
0 (Viral Nonstructural Proteins)
تواريخ الأحداث: Date Created: 20221222 Date Completed: 20230119 Latest Revision: 20231207
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9841423
DOI: 10.1093/nar/gkac1177
PMID: 36546762
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkac1177