Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.
Identifieur interne : 000195 ( PubMed/Curation ); précédent : 000194; suivant : 000196Remdesivir 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.
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
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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></affiliation></author><author><name sortKey="Ferron, Francois" sort="Ferron, Francois" uniqKey="Ferron F" first="Francois" last="Ferron">Francois Ferron</name><affiliation wicri:level="1"><nlm:affiliation>Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 163 Avenue de Luminy, 13288, Marseille, France. 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active-sites.</title><author><name sortKey="Shannon, Ashleigh" sort="Shannon, Ashleigh" uniqKey="Shannon A" first="Ashleigh" last="Shannon">Ashleigh Shannon</name><affiliation wicri:level="1"><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></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="1"><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></affiliation></author><author><name sortKey="Selisko, Barbara" sort="Selisko, Barbara" uniqKey="Selisko B" first="Barbara" last="Selisko">Barbara Selisko</name><affiliation wicri:level="1"><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></affiliation></author><author><name sortKey="Eydoux, Cecilia" sort="Eydoux, Cecilia" uniqKey="Eydoux C" first="Cecilia" last="Eydoux">Cecilia Eydoux</name><affiliation wicri:level="1"><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></affiliation></author><author><name sortKey="Alvarez, Karine" sort="Alvarez, Karine" uniqKey="Alvarez K" first="Karine" last="Alvarez">Karine Alvarez</name><affiliation wicri:level="1"><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></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="1"><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></affiliation></author><author><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><affiliation wicri:level="1"><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></affiliation></author><author><name sortKey="Peersen, Olve" sort="Peersen, Olve" uniqKey="Peersen O" first="Olve" last="Peersen">Olve Peersen</name><affiliation wicri:level="1"><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></affiliation></author><author><name sortKey="Ferron, Francois" sort="Ferron, Francois" uniqKey="Ferron F" first="Francois" last="Ferron">Francois Ferron</name><affiliation wicri:level="1"><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></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="1"><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></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></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="Publisher" Owner="NLM"><PMID Version="1">32283108</PMID><DateRevised><Year>2020</Year><Month>04</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1872-9096</ISSN><JournalIssue CitedMedium="Internet"><Volume>178</Volume><PubDate><Year>2020</Year><Month>Apr</Month><Day>10</Day></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><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">COVID-19</Keyword><Keyword MajorTopicYN="N">Coronavirus</Keyword><Keyword MajorTopicYN="N">Exonuclease</Keyword><Keyword MajorTopicYN="N">Mutation</Keyword><Keyword MajorTopicYN="N">Nucleotide analogue</Keyword><Keyword MajorTopicYN="N">RNA-Dependent RNA polymerase</Keyword><Keyword MajorTopicYN="N">Remdesivir</Keyword><Keyword MajorTopicYN="N">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>4</Month><Day>14</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>aheadofprint</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></record>Pour manipuler ce document sous Unix (Dilib)
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