Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.
Identifieur interne : 000774 ( Main/Exploration ); précédent : 000773; suivant : 000775Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.
Auteurs : Ashleigh Shannon [France] ; Nhung Thi-Tuyet Le [France] ; Barbara Selisko [France] ; Cecilia Eydoux [France] ; Karine Alvarez [France] ; Jean-Claude Guillemot [France] ; Etienne Decroly [France] ; Olve Peersen [France] ; Francois Ferron [France] ; Bruno Canard [France]Source :
- Antiviral research [ 1872-9096 ] ; 2020.
Descripteurs français
- KwdFr :
- AMP (analogues et dérivés), AMP (composition chimique), AMP (pharmacologie), ARN viral (composition chimique), ARN viral (génétique), Alanine (analogues et dérivés), Alanine (composition chimique), Alanine (pharmacologie), Antimétabolites (composition chimique), Antimétabolites (pharmacologie), Antiviraux (composition chimique), Antiviraux (pharmacologie), Betacoronavirus (composition chimique), Betacoronavirus (effets des médicaments et des substances chimiques), Betacoronavirus (génétique), Betacoronavirus (métabolisme), Conformation des protéines (MeSH), Domaine catalytique (MeSH), Exoribonucleases (composition chimique), Exoribonucleases (génétique), Exoribonucleases (métabolisme), Humains (MeSH), Infections à coronavirus (traitement médicamenteux), Infections à coronavirus (virologie), Modèles moléculaires (MeSH), Mutation (MeSH), Pandémies (MeSH), Pneumopathie virale (traitement médicamenteux), Pneumopathie virale (virologie), Protéines virales non structurales (composition chimique), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), RNA replicase (composition chimique), RNA replicase (génétique), RNA replicase (métabolisme), Relation structure-activité (MeSH), Résistance virale aux médicaments (MeSH).
- MESH :
- analogues et dérivés : AMP, Alanine.
- composition chimique : AMP, ARN viral, Alanine, Antimétabolites, Antiviraux, Betacoronavirus, Exoribonucleases, Protéines virales non structurales, RNA replicase.
- effets des médicaments et des substances chimiques : Betacoronavirus.
- génétique : ARN viral, Betacoronavirus, Exoribonucleases, Protéines virales non structurales, RNA replicase.
- métabolisme : Betacoronavirus, Exoribonucleases, Protéines virales non structurales, RNA replicase.
- pharmacologie : AMP, Alanine, Antimétabolites, Antiviraux.
- traitement médicamenteux : Infections à coronavirus, Pneumopathie virale.
- virologie : Infections à coronavirus, Pneumopathie virale.
- Conformation des protéines, Domaine catalytique, Humains, Modèles moléculaires, Mutation, Pandémies, Relation structure-activité, Résistance virale aux médicaments.
English descriptors
- KwdEn :
- Adenosine Monophosphate (analogs & derivatives), Adenosine Monophosphate (chemistry), Adenosine Monophosphate (pharmacology), Alanine (analogs & derivatives), Alanine (chemistry), Alanine (pharmacology), Antimetabolites (chemistry), Antimetabolites (pharmacology), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Betacoronavirus (chemistry), Betacoronavirus (drug effects), Betacoronavirus (genetics), Betacoronavirus (metabolism), Catalytic Domain (MeSH), Coronavirus Infections (drug therapy), Coronavirus Infections (virology), Drug Resistance, Viral (MeSH), Exoribonucleases (chemistry), Exoribonucleases (genetics), Exoribonucleases (metabolism), Humans (MeSH), Models, Molecular (MeSH), Mutation (MeSH), Pandemics (MeSH), Pneumonia, Viral (drug therapy), Pneumonia, Viral (virology), Protein Conformation (MeSH), RNA Replicase (chemistry), RNA Replicase (genetics), RNA Replicase (metabolism), RNA, Viral (chemistry), RNA, Viral (genetics), Structure-Activity Relationship (MeSH), Viral Nonstructural Proteins (chemistry), Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism).
- MESH :
- chemical , analogs & derivatives : Adenosine Monophosphate, Alanine.
- chemical , chemistry : Adenosine Monophosphate, Alanine, Antimetabolites, Antiviral Agents, Exoribonucleases, RNA Replicase, RNA, Viral, Viral Nonstructural Proteins.
- chemical , genetics : Exoribonucleases, RNA Replicase, RNA, Viral, Viral Nonstructural Proteins.
- chemical , metabolism : Exoribonucleases, RNA Replicase, Viral Nonstructural Proteins.
- chemical , pharmacology : Adenosine Monophosphate, Alanine, Antimetabolites, Antiviral Agents.
- chemistry : Betacoronavirus.
- drug effects : Betacoronavirus.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- genetics : Betacoronavirus.
- metabolism : Betacoronavirus.
- virology : Coronavirus Infections, Pneumonia, Viral.
- Catalytic Domain, Drug Resistance, Viral, Humans, Models, Molecular, Mutation, Pandemics, Protein Conformation, Structure-Activity Relationship.
Abstract
The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.
DOI: 10.1016/j.antiviral.2020.104793
PubMed: 32283108
PubMed Central: PMC7151495
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Peersen, Olve" sort="Peersen, Olve" uniqKey="Peersen O" first="Olve" last="Peersen">Olve Peersen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA; Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA; Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Ferron, Francois" sort="Ferron, Francois" uniqKey="Ferron F" first="Francois" last="Ferron">Francois Ferron</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: francois.ferron@afmb.univ-mrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: bruno.canard@afmb.univ-mrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32283108</idno><idno type="pmid">32283108</idno><idno type="doi">10.1016/j.antiviral.2020.104793</idno><idno type="pmc">PMC7151495</idno><idno type="wicri:Area/Main/Corpus">001739</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">001739</idno><idno type="wicri:Area/Main/Curation">001739</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">001739</idno><idno type="wicri:Area/Main/Exploration">001739</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.</title><author><name sortKey="Shannon, Ashleigh" sort="Shannon, Ashleigh" uniqKey="Shannon A" first="Ashleigh" last="Shannon">Ashleigh Shannon</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Le, Nhung Thi Tuyet" sort="Le, Nhung Thi Tuyet" uniqKey="Le N" first="Nhung Thi-Tuyet" last="Le">Nhung Thi-Tuyet Le</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Selisko, Barbara" sort="Selisko, Barbara" uniqKey="Selisko B" first="Barbara" last="Selisko">Barbara Selisko</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Eydoux, Cecilia" sort="Eydoux, Cecilia" uniqKey="Eydoux C" first="Cecilia" last="Eydoux">Cecilia Eydoux</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Alvarez, Karine" sort="Alvarez, Karine" uniqKey="Alvarez K" first="Karine" last="Alvarez">Karine Alvarez</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Peersen, Olve" sort="Peersen, Olve" uniqKey="Peersen O" first="Olve" last="Peersen">Olve Peersen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA; Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA; Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Ferron, Francois" sort="Ferron, Francois" uniqKey="Ferron F" first="Francois" last="Ferron">Francois Ferron</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: francois.ferron@afmb.univ-mrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="4"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: bruno.canard@afmb.univ-mrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author></analytic><series><title level="j">Antiviral research</title><idno type="eISSN">1872-9096</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine Monophosphate (analogs & derivatives)</term><term>Adenosine Monophosphate (chemistry)</term><term>Adenosine Monophosphate (pharmacology)</term><term>Alanine (analogs & derivatives)</term><term>Alanine (chemistry)</term><term>Alanine (pharmacology)</term><term>Antimetabolites (chemistry)</term><term>Antimetabolites (pharmacology)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Betacoronavirus (chemistry)</term><term>Betacoronavirus (drug effects)</term><term>Betacoronavirus (genetics)</term><term>Betacoronavirus (metabolism)</term><term>Catalytic Domain (MeSH)</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus Infections (virology)</term><term>Drug Resistance, Viral (MeSH)</term><term>Exoribonucleases (chemistry)</term><term>Exoribonucleases (genetics)</term><term>Exoribonucleases (metabolism)</term><term>Humans (MeSH)</term><term>Models, Molecular (MeSH)</term><term>Mutation (MeSH)</term><term>Pandemics (MeSH)</term><term>Pneumonia, Viral (drug therapy)</term><term>Pneumonia, Viral (virology)</term><term>Protein Conformation (MeSH)</term><term>RNA Replicase (chemistry)</term><term>RNA Replicase (genetics)</term><term>RNA Replicase (metabolism)</term><term>RNA, Viral (chemistry)</term><term>RNA, Viral (genetics)</term><term>Structure-Activity Relationship (MeSH)</term><term>Viral Nonstructural Proteins (chemistry)</term><term>Viral Nonstructural Proteins (genetics)</term><term>Viral Nonstructural Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>AMP (analogues et dérivés)</term><term>AMP (composition chimique)</term><term>AMP (pharmacologie)</term><term>ARN viral (composition chimique)</term><term>ARN viral (génétique)</term><term>Alanine (analogues et dérivés)</term><term>Alanine (composition chimique)</term><term>Alanine (pharmacologie)</term><term>Antimétabolites (composition chimique)</term><term>Antimétabolites (pharmacologie)</term><term>Antiviraux (composition chimique)</term><term>Antiviraux (pharmacologie)</term><term>Betacoronavirus (composition chimique)</term><term>Betacoronavirus (effets des médicaments et des substances chimiques)</term><term>Betacoronavirus (génétique)</term><term>Betacoronavirus (métabolisme)</term><term>Conformation des protéines (MeSH)</term><term>Domaine catalytique (MeSH)</term><term>Exoribonucleases (composition chimique)</term><term>Exoribonucleases (génétique)</term><term>Exoribonucleases (métabolisme)</term><term>Humains (MeSH)</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Infections à coronavirus (virologie)</term><term>Modèles moléculaires (MeSH)</term><term>Mutation (MeSH)</term><term>Pandémies (MeSH)</term><term>Pneumopathie virale (traitement médicamenteux)</term><term>Pneumopathie virale (virologie)</term><term>Protéines virales non structurales (composition chimique)</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>RNA replicase (composition chimique)</term><term>RNA replicase (génétique)</term><term>RNA replicase (métabolisme)</term><term>Relation structure-activité (MeSH)</term><term>Résistance virale aux médicaments (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adenosine Monophosphate</term><term>Alanine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Adenosine Monophosphate</term><term>Alanine</term><term>Antimetabolites</term><term>Antiviral Agents</term><term>Exoribonucleases</term><term>RNA Replicase</term><term>RNA, Viral</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Exoribonucleases</term><term>RNA Replicase</term><term>RNA, Viral</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Exoribonucleases</term><term>RNA Replicase</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenosine Monophosphate</term><term>Alanine</term><term>Antimetabolites</term><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>AMP</term><term>Alanine</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>AMP</term><term>ARN viral</term><term>Alanine</term><term>Antimétabolites</term><term>Antiviraux</term><term>Betacoronavirus</term><term>Exoribonucleases</term><term>Protéines virales non structurales</term><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN viral</term><term>Betacoronavirus</term><term>Exoribonucleases</term><term>Protéines virales non structurales</term><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Betacoronavirus</term><term>Exoribonucleases</term><term>Protéines virales non structurales</term><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>AMP</term><term>Alanine</term><term>Antimétabolites</term><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term><term>Pneumopathie virale</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term><term>Pneumopathie virale</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term><term>Drug Resistance, Viral</term><term>Humans</term><term>Models, Molecular</term><term>Mutation</term><term>Pandemics</term><term>Protein Conformation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conformation des protéines</term><term>Domaine catalytique</term><term>Humains</term><term>Modèles moléculaires</term><term>Mutation</term><term>Pandémies</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32283108</PMID><DateCompleted><Year>2020</Year><Month>07</Month><Day>06</Day></DateCompleted><DateRevised><Year>2020</Year><Month>07</Month><Day>06</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1872-9096</ISSN><JournalIssue CitedMedium="Internet"><Volume>178</Volume><PubDate><Year>2020</Year><Month>06</Month></PubDate></JournalIssue><Title>Antiviral research</Title><ISOAbbreviation>Antiviral Res.</ISOAbbreviation></Journal><ArticleTitle>Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.</ArticleTitle><Pagination><MedlinePgn>104793</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0166-3542(20)30207-2</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.antiviral.2020.104793</ELocationID><Abstract><AbstractText>The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.</AbstractText><CopyrightInformation>Copyright © 2020 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Shannon</LastName><ForeName>Ashleigh</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Le</LastName><ForeName>Nhung Thi-Tuyet</ForeName><Initials>NT</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Selisko</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Eydoux</LastName><ForeName>Cecilia</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alvarez</LastName><ForeName>Karine</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guillemot</LastName><ForeName>Jean-Claude</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Decroly</LastName><ForeName>Etienne</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peersen</LastName><ForeName>Olve</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA; Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ferron</LastName><ForeName>Francois</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: francois.ferron@afmb.univ-mrs.fr.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Canard</LastName><ForeName>Bruno</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address: bruno.canard@afmb.univ-mrs.fr.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>04</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Antiviral Res</MedlineTA><NlmUniqueID>8109699</NlmUniqueID><ISSNLinking>0166-3542</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000963">Antimetabolites</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D012367">RNA, Viral</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017361">Viral Nonstructural 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UI="D000409">Alanine</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Disease" UI="C000657245">COVID-19</SupplMeshName><SupplMeshName Type="Organism" UI="C000656484">severe acute respiratory syndrome coronavirus 2</SupplMeshName></SupplMeshList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000249" MajorTopicYN="N">Adenosine Monophosphate</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000409" MajorTopicYN="N">Alanine</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000963" MajorTopicYN="N">Antimetabolites</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D024882" MajorTopicYN="N">Drug Resistance, Viral</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005095" MajorTopicYN="N">Exoribonucleases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" 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MajorTopicYN="Y">Resistance</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>03</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2020</Year><Month>04</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>04</Month><Day>05</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>4</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>7</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>4</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32283108</ArticleId><ArticleId IdType="pii">S0166-3542(20)30207-2</ArticleId><ArticleId IdType="doi">10.1016/j.antiviral.2020.104793</ArticleId><ArticleId IdType="pmc">PMC7151495</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>France</li></country><region><li>Provence-Alpes-Côte d'Azur</li></region><settlement><li>Marseille</li></settlement><orgName><li>Université d'Aix-Marseille</li></orgName></list><tree><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Shannon, Ashleigh" sort="Shannon, Ashleigh" uniqKey="Shannon A" first="Ashleigh" last="Shannon">Ashleigh Shannon</name></region><name sortKey="Alvarez, Karine" sort="Alvarez, Karine" uniqKey="Alvarez K" first="Karine" last="Alvarez">Karine Alvarez</name><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><name sortKey="Eydoux, Cecilia" sort="Eydoux, Cecilia" uniqKey="Eydoux C" first="Cecilia" last="Eydoux">Cecilia Eydoux</name><name sortKey="Ferron, Francois" sort="Ferron, Francois" uniqKey="Ferron F" first="Francois" last="Ferron">Francois Ferron</name><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><name sortKey="Le, Nhung Thi Tuyet" sort="Le, Nhung Thi Tuyet" uniqKey="Le N" first="Nhung Thi-Tuyet" last="Le">Nhung Thi-Tuyet Le</name><name sortKey="Peersen, Olve" sort="Peersen, Olve" uniqKey="Peersen O" first="Olve" last="Peersen">Olve Peersen</name><name sortKey="Selisko, Barbara" sort="Selisko, Barbara" uniqKey="Selisko B" first="Barbara" last="Selisko">Barbara Selisko</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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