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Basic Characteristics of Mutations
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Mutation Site
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I87V |
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Mutation Site Sentence
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The T21I+T304I virus acquired a nsp14 exonuclease I87V mutation, which existed in the T21I+S144A+T304I triple mutant that appeared in later passages, further supporting a stepwise selection (table S1). |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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NSP14 |
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Standardized Encoding Gene
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ORF1b
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Genotype/Subtype
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- |
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Viral Reference
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MN908947.3
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Functional Impact and Mechanisms
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Disease
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Cell line
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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- |
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Location
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- |
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Literature Information
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PMID
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39047088
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Title
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In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance
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Author
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Zhu Y,Yurgelonis I,Noell S,Yang Q,Guan S,Li Z,Hao L,Rothan H,Rai DK,McMonagle P,Baniecki ML,Greasley SE,Plotnikova O,Lee J,Nicki JA,Ferre R,Byrnes LJ,Liu W,Craig TK,Steppan CM,Liberator P,Soares HD,Allerton CMN,Anderson AS,Cardin RD
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Journal
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Science advances
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Journal Info
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2024 Jul 26;10(30):eadl4013
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Abstract
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To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus M(pro) inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M(pro) mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and M(pro) activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.
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Sequence Data
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PRJNA1079806
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