Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance.
Identifieur interne : 000F50 ( PubMed/Curation ); précédent : 000F49; suivant : 000F51Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance.
Auteurs : Xufang Deng [États-Unis] ; Sarah E. Stjohn [États-Unis] ; Heather L. Osswald [États-Unis] ; Amornrat O'Brien [États-Unis] ; Bridget S. Banach [États-Unis] ; Katrina Sleeman [États-Unis] ; Arun K. Ghosh [États-Unis] ; Andrew D. Mesecar [États-Unis] ; Susan C. Baker [États-Unis]Source :
- Journal of virology [ 1098-5514 ] ; 2014.
Descripteurs français
- KwdFr :
- MESH :
- génétique : Coronavirus.
- pharmacologie : Inhibiteurs de protéases.
- physiologie : Coronavirus.
- Animaux, Coronavirus, Cricetinae, Humains, Lignée cellulaire, Lignée cellulaire tumorale, Réplication virale, Résistance virale aux médicaments, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- MESH :
- chemical , pharmacology : Protease Inhibitors.
- drug effects : Coronavirus.
- genetics : Coronavirus.
- physiology : Coronavirus.
- Animals, Cell Line, Cell Line, Tumor, Cricetinae, Drug Resistance, Viral, Humans, Mice, Mice, Inbred C57BL, Virus Replication.
Abstract
Viral protease inhibitors are remarkably effective at blocking the replication of viruses such as human immunodeficiency virus and hepatitis C virus, but they inevitably lead to the selection of inhibitor-resistant mutants, which may contribute to ongoing disease. Protease inhibitors blocking the replication of coronavirus (CoV), including the causative agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), provide a promising foundation for the development of anticoronaviral therapeutics. However, the selection and consequences of inhibitor-resistant CoVs are unknown. In this study, we exploited the model coronavirus, mouse hepatitis virus (MHV), to investigate the genotype and phenotype of MHV quasispecies selected for resistance to a broad-spectrum CoV 3C-like protease (3CLpro) inhibitor. Clonal sequencing identified single or double mutations within the 3CLpro coding sequence of inhibitor-resistant virus. Using reverse genetics to generate isogenic viruses with mutant 3CLpros, we found that viruses encoding double-mutant 3CLpros are fully resistant to the inhibitor and exhibit a significant delay in proteolytic processing of the viral replicase polyprotein. The inhibitor-resistant viruses also exhibited postponed and reduced production of infectious virus particles. Biochemical analysis verified double-mutant 3CLpro enzyme as impaired for protease activity and exhibiting reduced sensitivity to the inhibitor and revealed a delayed kinetics of inhibitor hydrolysis and activity restoration. Furthermore, the inhibitor-resistant virus was shown to be highly attenuated in mice. Our study provides the first insight into the pathogenicity and mechanism of 3CLpro inhibitor-resistant CoV mutants, revealing a low genetic barrier but high fitness cost of resistance. Importance: RNA viruses are infamous for their ability to evolve in response to selective pressure, such as the presence of antiviral drugs. For coronaviruses such as the causative agent of Middle East respiratory syndrome (MERS), protease inhibitors have been developed and shown to block virus replication, but the consequences of selection of inhibitor-resistant mutants have not been studied. Here, we report the low genetic barrier and relatively high deleterious consequences of CoV resistance to a 3CLpro protease inhibitor in a coronavirus model system, mouse hepatitis virus (MHV). We found that although mutations that confer resistance arise quickly, the resistant viruses replicate slowly and do not cause lethal disease in mice. Overall, our study provides the first analysis of the low barrier but high cost of resistance to a CoV 3CLpro inhibitor, which will facilitate the further development of protease inhibitors as anti-coronavirus therapeutics.
DOI: 10.1128/JVI.01528-14
PubMed: 25100843
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000F50
Links to Exploration step
pubmed:25100843Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance.</title>
<author><name sortKey="Deng, Xufang" sort="Deng, Xufang" uniqKey="Deng X" first="Xufang" last="Deng">Xufang Deng</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stjohn, Sarah E" sort="Stjohn, Sarah E" uniqKey="Stjohn S" first="Sarah E" last="Stjohn">Sarah E. Stjohn</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Osswald, Heather L" sort="Osswald, Heather L" uniqKey="Osswald H" first="Heather L" last="Osswald">Heather L. Osswald</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="O Brien, Amornrat" sort="O Brien, Amornrat" uniqKey="O Brien A" first="Amornrat" last="O'Brien">Amornrat O'Brien</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Banach, Bridget S" sort="Banach, Bridget S" uniqKey="Banach B" first="Bridget S" last="Banach">Bridget S. Banach</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA sbaker1@luc.edu.</nlm:affiliation>
<country wicri:rule="url">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2014">2014</date>
<idno type="RBID">pubmed:25100843</idno>
<idno type="pmid">25100843</idno>
<idno type="doi">10.1128/JVI.01528-14</idno>
<idno type="wicri:Area/PubMed/Corpus">000F50</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F50</idno>
<idno type="wicri:Area/PubMed/Curation">000F50</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F50</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance.</title>
<author><name sortKey="Deng, Xufang" sort="Deng, Xufang" uniqKey="Deng X" first="Xufang" last="Deng">Xufang Deng</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stjohn, Sarah E" sort="Stjohn, Sarah E" uniqKey="Stjohn S" first="Sarah E" last="Stjohn">Sarah E. Stjohn</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Osswald, Heather L" sort="Osswald, Heather L" uniqKey="Osswald H" first="Heather L" last="Osswald">Heather L. Osswald</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="O Brien, Amornrat" sort="O Brien, Amornrat" uniqKey="O Brien A" first="Amornrat" last="O'Brien">Amornrat O'Brien</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Banach, Bridget S" sort="Banach, Bridget S" uniqKey="Banach B" first="Bridget S" last="Banach">Bridget S. Banach</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA sbaker1@luc.edu.</nlm:affiliation>
<country wicri:rule="url">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of virology</title>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2014" type="published">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Cell Line, Tumor</term>
<term>Coronavirus (drug effects)</term>
<term>Coronavirus (genetics)</term>
<term>Coronavirus (physiology)</term>
<term>Cricetinae</term>
<term>Drug Resistance, Viral</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Protease Inhibitors (pharmacology)</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Coronavirus ()</term>
<term>Coronavirus (génétique)</term>
<term>Coronavirus (physiologie)</term>
<term>Cricetinae</term>
<term>Humains</term>
<term>Inhibiteurs de protéases (pharmacologie)</term>
<term>Lignée cellulaire</term>
<term>Lignée cellulaire tumorale</term>
<term>Réplication virale</term>
<term>Résistance virale aux médicaments</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de protéases</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Cell Line, Tumor</term>
<term>Cricetinae</term>
<term>Drug Resistance, Viral</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Coronavirus</term>
<term>Cricetinae</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Lignée cellulaire tumorale</term>
<term>Réplication virale</term>
<term>Résistance virale aux médicaments</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Viral protease inhibitors are remarkably effective at blocking the replication of viruses such as human immunodeficiency virus and hepatitis C virus, but they inevitably lead to the selection of inhibitor-resistant mutants, which may contribute to ongoing disease. Protease inhibitors blocking the replication of coronavirus (CoV), including the causative agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), provide a promising foundation for the development of anticoronaviral therapeutics. However, the selection and consequences of inhibitor-resistant CoVs are unknown. In this study, we exploited the model coronavirus, mouse hepatitis virus (MHV), to investigate the genotype and phenotype of MHV quasispecies selected for resistance to a broad-spectrum CoV 3C-like protease (3CLpro) inhibitor. Clonal sequencing identified single or double mutations within the 3CLpro coding sequence of inhibitor-resistant virus. Using reverse genetics to generate isogenic viruses with mutant 3CLpros, we found that viruses encoding double-mutant 3CLpros are fully resistant to the inhibitor and exhibit a significant delay in proteolytic processing of the viral replicase polyprotein. The inhibitor-resistant viruses also exhibited postponed and reduced production of infectious virus particles. Biochemical analysis verified double-mutant 3CLpro enzyme as impaired for protease activity and exhibiting reduced sensitivity to the inhibitor and revealed a delayed kinetics of inhibitor hydrolysis and activity restoration. Furthermore, the inhibitor-resistant virus was shown to be highly attenuated in mice. Our study provides the first insight into the pathogenicity and mechanism of 3CLpro inhibitor-resistant CoV mutants, revealing a low genetic barrier but high fitness cost of resistance. Importance: RNA viruses are infamous for their ability to evolve in response to selective pressure, such as the presence of antiviral drugs. For coronaviruses such as the causative agent of Middle East respiratory syndrome (MERS), protease inhibitors have been developed and shown to block virus replication, but the consequences of selection of inhibitor-resistant mutants have not been studied. Here, we report the low genetic barrier and relatively high deleterious consequences of CoV resistance to a 3CLpro protease inhibitor in a coronavirus model system, mouse hepatitis virus (MHV). We found that although mutations that confer resistance arise quickly, the resistant viruses replicate slowly and do not cause lethal disease in mice. Overall, our study provides the first analysis of the low barrier but high cost of resistance to a CoV 3CLpro inhibitor, which will facilitate the further development of protease inhibitors as anti-coronavirus therapeutics.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25100843</PMID>
<DateCompleted><Year>2014</Year>
<Month>11</Month>
<Day>25</Day>
</DateCompleted>
<DateRevised><Year>2018</Year>
<Month>11</Month>
<Day>13</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1098-5514</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>88</Volume>
<Issue>20</Issue>
<PubDate><Year>2014</Year>
<Month>Oct</Month>
</PubDate>
</JournalIssue>
<Title>Journal of virology</Title>
<ISOAbbreviation>J. Virol.</ISOAbbreviation>
</Journal>
<ArticleTitle>Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance.</ArticleTitle>
<Pagination><MedlinePgn>11886-98</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1128/JVI.01528-14</ELocationID>
<Abstract><AbstractText>Viral protease inhibitors are remarkably effective at blocking the replication of viruses such as human immunodeficiency virus and hepatitis C virus, but they inevitably lead to the selection of inhibitor-resistant mutants, which may contribute to ongoing disease. Protease inhibitors blocking the replication of coronavirus (CoV), including the causative agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), provide a promising foundation for the development of anticoronaviral therapeutics. However, the selection and consequences of inhibitor-resistant CoVs are unknown. In this study, we exploited the model coronavirus, mouse hepatitis virus (MHV), to investigate the genotype and phenotype of MHV quasispecies selected for resistance to a broad-spectrum CoV 3C-like protease (3CLpro) inhibitor. Clonal sequencing identified single or double mutations within the 3CLpro coding sequence of inhibitor-resistant virus. Using reverse genetics to generate isogenic viruses with mutant 3CLpros, we found that viruses encoding double-mutant 3CLpros are fully resistant to the inhibitor and exhibit a significant delay in proteolytic processing of the viral replicase polyprotein. The inhibitor-resistant viruses also exhibited postponed and reduced production of infectious virus particles. Biochemical analysis verified double-mutant 3CLpro enzyme as impaired for protease activity and exhibiting reduced sensitivity to the inhibitor and revealed a delayed kinetics of inhibitor hydrolysis and activity restoration. Furthermore, the inhibitor-resistant virus was shown to be highly attenuated in mice. Our study provides the first insight into the pathogenicity and mechanism of 3CLpro inhibitor-resistant CoV mutants, revealing a low genetic barrier but high fitness cost of resistance. Importance: RNA viruses are infamous for their ability to evolve in response to selective pressure, such as the presence of antiviral drugs. For coronaviruses such as the causative agent of Middle East respiratory syndrome (MERS), protease inhibitors have been developed and shown to block virus replication, but the consequences of selection of inhibitor-resistant mutants have not been studied. Here, we report the low genetic barrier and relatively high deleterious consequences of CoV resistance to a 3CLpro protease inhibitor in a coronavirus model system, mouse hepatitis virus (MHV). We found that although mutations that confer resistance arise quickly, the resistant viruses replicate slowly and do not cause lethal disease in mice. Overall, our study provides the first analysis of the low barrier but high cost of resistance to a CoV 3CLpro inhibitor, which will facilitate the further development of protease inhibitors as anti-coronavirus therapeutics.</AbstractText>
<CopyrightInformation>Copyright © 2014, American Society for Microbiology. All Rights Reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Deng</LastName>
<ForeName>Xufang</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>StJohn</LastName>
<ForeName>Sarah E</ForeName>
<Initials>SE</Initials>
<AffiliationInfo><Affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Osswald</LastName>
<ForeName>Heather L</ForeName>
<Initials>HL</Initials>
<AffiliationInfo><Affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>O'Brien</LastName>
<ForeName>Amornrat</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Banach</LastName>
<ForeName>Bridget S</ForeName>
<Initials>BS</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sleeman</LastName>
<ForeName>Katrina</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ghosh</LastName>
<ForeName>Arun K</ForeName>
<Initials>AK</Initials>
<AffiliationInfo><Affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mesecar</LastName>
<ForeName>Andrew D</ForeName>
<Initials>AD</Initials>
<AffiliationInfo><Affiliation>Departments of Biological Science and Chemistry, Purdue University, West Lafayette, Indiana, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Baker</LastName>
<ForeName>Susan C</ForeName>
<Initials>SC</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA sbaker1@luc.edu.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R01 AI026603</GrantID>
<Acronym>AI</Acronym>
<Agency>NIAID NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 AI085089</GrantID>
<Acronym>AI</Acronym>
<Agency>NIAID NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>AI085089</GrantID>
<Acronym>AI</Acronym>
<Agency>NIAID NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>AI026603</GrantID>
<Acronym>AI</Acronym>
<Agency>NIAID NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R37 GM053386</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2014</Year>
<Month>08</Month>
<Day>06</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Virol</MedlineTA>
<NlmUniqueID>0113724</NlmUniqueID>
<ISSNLinking>0022-538X</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011480">Protease Inhibitors</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017934" MajorTopicYN="N">Coronavirus</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006224" MajorTopicYN="N">Cricetinae</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D024882" MajorTopicYN="N">Drug Resistance, Viral</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011480" MajorTopicYN="N">Protease Inhibitors</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014779" MajorTopicYN="Y">Virus Replication</DescriptorName>
</MeshHeading>
</MeshHeadingList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2014</Year>
<Month>8</Month>
<Day>8</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2014</Year>
<Month>8</Month>
<Day>8</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2014</Year>
<Month>12</Month>
<Day>15</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">25100843</ArticleId>
<ArticleId IdType="pii">JVI.01528-14</ArticleId>
<ArticleId IdType="doi">10.1128/JVI.01528-14</ArticleId>
<ArticleId IdType="pmc">PMC4178758</ArticleId>
</ArticleIdList>
<ReferenceList><Reference><Citation>J Virol. 2008 Mar;82(5):2515-27</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18094151</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Virus Res. 2014 Dec 19;194:184-90</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24512893</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2008 Sep;82(17):8647-55</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18562531</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Bioorg Med Chem Lett. 2008 Oct 15;18(20):5684-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18796354</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Gen Virol. 2000 Apr;81(Pt 4):853-79</Citation>
<ArticleIdList><ArticleId IdType="pubmed">10725411</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2002 Apr;76(8):3697-708</Citation>
<ArticleIdList><ArticleId IdType="pubmed">11907209</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>EMBO J. 2002 Jul 1;21(13):3213-24</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12093723</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2002 Nov;76(21):11065-78</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12368349</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Lancet. 2003 May 24;361(9371):1767-72</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12781535</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Science. 2003 Jun 13;300(5626):1763-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12746549</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13190-5</Citation>
<ArticleIdList><ArticleId IdType="pubmed">14585926</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Med. 2004 Apr;10(4):368-73</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15034574</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6212-6</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15073334</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 1967 Dec;58(6):2268-73</Citation>
<ArticleIdList><ArticleId IdType="pubmed">4298953</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 1967 Oct;1(5):1019-27</Citation>
<ArticleIdList><ArticleId IdType="pubmed">5630226</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Arch Gesamte Virusforsch. 1974;44(3):298-302</Citation>
<ArticleIdList><ArticleId IdType="pubmed">4365902</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Virology. 1998 Mar 15;242(2):288-302</Citation>
<ArticleIdList><ArticleId IdType="pubmed">9514967</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochemistry. 2004 Nov 30;43(47):14958-70</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15554703</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Med. 2004 Dec;10(12 Suppl):S88-97</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15577937</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2005 Jan;79(2):884-95</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15613317</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Biol Chem. 2005 Jun 17;280(24):22741-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15831489</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Med Chem. 2005 Nov 3;48(22):6767-71</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16250632</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Clin Infect Dis. 2006 Oct 15;43(8):1009-15</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16983613</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Blood. 2007 Feb 1;109(3):1131-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16985170</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochemistry. 2007 Jul 31;46(30):8744-52</Citation>
<ArticleIdList><ArticleId IdType="pubmed">17605471</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Bioorg Med Chem Lett. 2007 Nov 1;17(21):5876-80</Citation>
<ArticleIdList><ArticleId IdType="pubmed">17855091</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16119-24</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18852458</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Hepatology. 2009 Dec;50(6):1709-18</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19787809</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Antimicrob Chemother. 2010 Feb;65(2):202-12</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19903720</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Sci Transl Med. 2010 May 5;2(30):30ra32</Citation>
<ArticleIdList><ArticleId IdType="pubmed">20445200</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Med Chem. 2010 Jul 8;53(13):4968-79</Citation>
<ArticleIdList><ArticleId IdType="pubmed">20527968</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20986-91</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21084633</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antimicrob Agents Chemother. 2011 Feb;55(2):459-72</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21078929</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Protein Cell. 2011 Apr;2(4):282-90</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21533772</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Hepatol. 2011 Jul;55(1):192-206</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21284949</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochem Soc Trans. 2011 Oct;39(5):1371-5</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21936817</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>PLoS Pathog. 2012;8(7):e1002832</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22910833</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14900-5</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22927388</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>N Engl J Med. 2012 Nov 8;367(19):1814-20</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23075143</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Med Chem. 2013 Jan 24;56(2):534-46</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23231439</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Eur J Med Chem. 2013 Jan;59:1-6</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23202846</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antiviral Res. 2013 Apr;98(1):93-120</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23403210</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2013 Jul;87(14):7790-2</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23678167</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Virol. 2013 Nov;87(21):11955-62</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23986593</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Curr Opin Virol. 2013 Oct;3(5):487-94</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24021560</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Bioorg Med Chem Lett. 2013 Nov 15;23(22):6172-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24080461</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Commun. 2013;4:2854</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24326875</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antiviral Res. 2014 Jan;101:105-12</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24269477</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>MBio. 2014;5(2):e00047-14</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24667706</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>N Engl J Med. 2014 Apr 17;370(16):1483-93</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24725238</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>MMWR Morb Mortal Wkly Rep. 2014 May 16;63(19):431-6</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24827411</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>N Engl J Med. 2014 May 15;370(20):1889-98</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24725239</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>N Engl J Med. 2014 May 22;370(21):1983-92</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24795200</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antimicrob Agents Chemother. 2014 Aug;58(8):4894-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24841268</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24841269</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24841273</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Chem Biol. 2008 Jun;15(6):597-606</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18559270</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
</PubmedData>
</pubmed>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/PubMed/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000F50 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd -nk 000F50 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= SrasV1 |flux= PubMed |étape= Curation |type= RBID |clé= pubmed:25100843 |texte= Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:25100843" \ | HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \ | NlmPubMed2Wicri -a SrasV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |