Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants
Identifieur interne : 000C31 ( Main/Exploration ); précédent : 000C30; suivant : 000C32Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants
Auteurs : Wei Zhang [Canada] ; Ben A. Bailey-Elkin [Canada] ; Robert C. M. Knaap [Pays-Bas] ; Baldeep Khare [Canada] ; Tim J. Dalebout [Pays-Bas] ; Garrett G. Johnson [Canada] ; Puck B. Van Kasteren [Pays-Bas] ; Nigel J. Mcleish [Canada] ; Jun Gu [Canada] ; Wenguang He [Canada] ; Marjolein Kikkert [Pays-Bas] ; Brian L. Mark [Canada] ; Sachdev S. Sidhu [Canada]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2017.
Descripteurs français
- KwdFr :
- Antienzymes (), Antienzymes (pharmacologie), Antiviraux (), Antiviraux (pharmacologie), Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Fièvre hémorragique de Crimée-Congo (métabolisme), Fièvre hémorragique de Crimée-Congo (virologie), Humains, Infections à coronavirus (métabolisme), Infections à coronavirus (virologie), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (génétique), Protéines virales (métabolisme), Ubiquitine (métabolisme), Ubiquitinylation (), Virus de la fièvre hémorragique de Crimée-Congo (), Virus de la fièvre hémorragique de Crimée-Congo (enzymologie), Virus de la fièvre hémorragique de Crimée-Congo (génétique), Évaluation préclinique de médicament.
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Virus de la fièvre hémorragique de Crimée-Congo.
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Protéines virales, Virus de la fièvre hémorragique de Crimée-Congo.
- métabolisme : Fièvre hémorragique de Crimée-Congo, Infections à coronavirus, Protéines virales, Ubiquitine.
- pharmacologie : Antienzymes, Antiviraux.
- virologie : Fièvre hémorragique de Crimée-Congo, Infections à coronavirus.
- Antienzymes, Antiviraux, Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Protéines virales, Ubiquitinylation, Virus de la fièvre hémorragique de Crimée-Congo, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Coronavirus Infections (metabolism), Coronavirus Infections (virology), Drug Evaluation, Preclinical, Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Hemorrhagic Fever Virus, Crimean-Congo (drug effects), Hemorrhagic Fever Virus, Crimean-Congo (enzymology), Hemorrhagic Fever Virus, Crimean-Congo (genetics), Hemorrhagic Fever, Crimean (metabolism), Hemorrhagic Fever, Crimean (virology), Humans, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (enzymology), Middle East Respiratory Syndrome Coronavirus (genetics), Ubiquitin (metabolism), Ubiquitination (drug effects), Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (genetics), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Antiviral Agents, Enzyme Inhibitors, Viral Proteins.
- chemical , genetics : Viral Proteins.
- chemical , metabolism : Ubiquitin, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors.
- drug effects : Hemorrhagic Fever Virus, Crimean-Congo, Middle East Respiratory Syndrome Coronavirus, Ubiquitination.
- enzymology : Hemorrhagic Fever Virus, Crimean-Congo, Middle East Respiratory Syndrome Coronavirus.
- genetics : Hemorrhagic Fever Virus, Crimean-Congo, Middle East Respiratory Syndrome Coronavirus.
- metabolism : Coronavirus Infections, Hemorrhagic Fever, Crimean.
- virology : Coronavirus Infections, Hemorrhagic Fever, Crimean.
- Drug Evaluation, Preclinical, Humans.
Abstract
The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.
Url:
DOI: 10.1371/journal.ppat.1006372
PubMed: 28542609
PubMed Central: 5451084
Affiliations:
- Canada, Pays-Bas
- Hollande-Méridionale, Manitoba, Ontario
- Leyde, Toronto, Winnipeg
- Université de Toronto, Université du Manitoba
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 001102
- to stream Pmc, to step Curation: 001102
- to stream Pmc, to step Checkpoint: 000745
- to stream PubMed, to step Corpus: 000C83
- to stream PubMed, to step Curation: 000C83
- to stream PubMed, to step Checkpoint: 000B67
- to stream Ncbi, to step Merge: 001A50
- to stream Ncbi, to step Curation: 001A50
- to stream Ncbi, to step Checkpoint: 001A50
- to stream Main, to step Merge: 000C34
- to stream Main, to step Curation: 000C31
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants</title>
<author><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bailey Elkin, Ben A" sort="Bailey Elkin, Ben A" uniqKey="Bailey Elkin B" first="Ben A." last="Bailey-Elkin">Ben A. Bailey-Elkin</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Knaap, Robert C M" sort="Knaap, Robert C M" uniqKey="Knaap R" first="Robert C. M." last="Knaap">Robert C. M. Knaap</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Khare, Baldeep" sort="Khare, Baldeep" uniqKey="Khare B" first="Baldeep" last="Khare">Baldeep Khare</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J." last="Dalebout">Tim J. Dalebout</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Johnson, Garrett G" sort="Johnson, Garrett G" uniqKey="Johnson G" first="Garrett G." last="Johnson">Garrett G. Johnson</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Kasteren, Puck B" sort="Van Kasteren, Puck B" uniqKey="Van Kasteren P" first="Puck B." last="Van Kasteren">Puck B. Van Kasteren</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mcleish, Nigel J" sort="Mcleish, Nigel J" uniqKey="Mcleish N" first="Nigel J." last="Mcleish">Nigel J. Mcleish</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gu, Jun" sort="Gu, Jun" uniqKey="Gu J" first="Jun" last="Gu">Jun Gu</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="He, Wenguang" sort="He, Wenguang" uniqKey="He W" first="Wenguang" last="He">Wenguang He</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L." last="Mark">Brian L. Mark</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sidhu, Sachdev S" sort="Sidhu, Sachdev S" uniqKey="Sidhu S" first="Sachdev S." last="Sidhu">Sachdev S. Sidhu</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">28542609</idno>
<idno type="pmc">5451084</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451084</idno>
<idno type="RBID">PMC:5451084</idno>
<idno type="doi">10.1371/journal.ppat.1006372</idno>
<date when="2017">2017</date>
<idno type="wicri:Area/Pmc/Corpus">001102</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001102</idno>
<idno type="wicri:Area/Pmc/Curation">001102</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001102</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000745</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000745</idno>
<idno type="wicri:source">PubMed</idno>
<idno type="RBID">pubmed:28542609</idno>
<idno type="wicri:Area/PubMed/Corpus">000C83</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000C83</idno>
<idno type="wicri:Area/PubMed/Curation">000C83</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000C83</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000B67</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000B67</idno>
<idno type="wicri:Area/Ncbi/Merge">001A50</idno>
<idno type="wicri:Area/Ncbi/Curation">001A50</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">001A50</idno>
<idno type="wicri:doubleKey">1553-7366:2017:Zhang W:potent:and:selective</idno>
<idno type="wicri:Area/Main/Merge">000C34</idno>
<idno type="wicri:Area/Main/Curation">000C31</idno>
<idno type="wicri:Area/Main/Exploration">000C31</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants</title>
<author><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bailey Elkin, Ben A" sort="Bailey Elkin, Ben A" uniqKey="Bailey Elkin B" first="Ben A." last="Bailey-Elkin">Ben A. Bailey-Elkin</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Knaap, Robert C M" sort="Knaap, Robert C M" uniqKey="Knaap R" first="Robert C. M." last="Knaap">Robert C. M. Knaap</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Khare, Baldeep" sort="Khare, Baldeep" uniqKey="Khare B" first="Baldeep" last="Khare">Baldeep Khare</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J." last="Dalebout">Tim J. Dalebout</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Johnson, Garrett G" sort="Johnson, Garrett G" uniqKey="Johnson G" first="Garrett G." last="Johnson">Garrett G. Johnson</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Kasteren, Puck B" sort="Van Kasteren, Puck B" uniqKey="Van Kasteren P" first="Puck B." last="Van Kasteren">Puck B. Van Kasteren</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mcleish, Nigel J" sort="Mcleish, Nigel J" uniqKey="Mcleish N" first="Nigel J." last="Mcleish">Nigel J. Mcleish</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gu, Jun" sort="Gu, Jun" uniqKey="Gu J" first="Jun" last="Gu">Jun Gu</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="He, Wenguang" sort="He, Wenguang" uniqKey="He W" first="Wenguang" last="He">Wenguang He</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name>
<affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea>
<placeName><settlement type="city">Leyde</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L." last="Mark">Brian L. Mark</name>
<affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea>
<orgName type="university">Université du Manitoba</orgName>
<placeName><settlement type="city">Winnipeg</settlement>
<region type="state">Manitoba</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sidhu, Sachdev S" sort="Sidhu, Sachdev S" uniqKey="Sidhu S" first="Sachdev S." last="Sidhu">Sachdev S. Sidhu</name>
<affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Pathogens</title>
<idno type="ISSN">1553-7366</idno>
<idno type="eISSN">1553-7374</idno>
<imprint><date when="2017">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Coronavirus Infections (metabolism)</term>
<term>Coronavirus Infections (virology)</term>
<term>Drug Evaluation, Preclinical</term>
<term>Enzyme Inhibitors (chemistry)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Hemorrhagic Fever Virus, Crimean-Congo (drug effects)</term>
<term>Hemorrhagic Fever Virus, Crimean-Congo (enzymology)</term>
<term>Hemorrhagic Fever Virus, Crimean-Congo (genetics)</term>
<term>Hemorrhagic Fever, Crimean (metabolism)</term>
<term>Hemorrhagic Fever, Crimean (virology)</term>
<term>Humans</term>
<term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term>
<term>Middle East Respiratory Syndrome Coronavirus (enzymology)</term>
<term>Middle East Respiratory Syndrome Coronavirus (genetics)</term>
<term>Ubiquitin (metabolism)</term>
<term>Ubiquitination (drug effects)</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
<term>Viral Proteins (genetics)</term>
<term>Viral Proteins (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes ()</term>
<term>Antienzymes (pharmacologie)</term>
<term>Antiviraux ()</term>
<term>Antiviraux (pharmacologie)</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie)</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term>
<term>Fièvre hémorragique de Crimée-Congo (métabolisme)</term>
<term>Fièvre hémorragique de Crimée-Congo (virologie)</term>
<term>Humains</term>
<term>Infections à coronavirus (métabolisme)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Protéines virales ()</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Protéines virales (génétique)</term>
<term>Protéines virales (métabolisme)</term>
<term>Ubiquitine (métabolisme)</term>
<term>Ubiquitinylation ()</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo ()</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo (enzymologie)</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo (génétique)</term>
<term>Évaluation préclinique de médicament</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Enzyme Inhibitors</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Ubiquitin</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Enzyme Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Hemorrhagic Fever Virus, Crimean-Congo</term>
<term>Middle East Respiratory Syndrome Coronavirus</term>
<term>Ubiquitination</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Hemorrhagic Fever Virus, Crimean-Congo</term>
<term>Middle East Respiratory Syndrome Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Hemorrhagic Fever Virus, Crimean-Congo</term>
<term>Middle East Respiratory Syndrome Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Protéines virales</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term>
<term>Hemorrhagic Fever, Crimean</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Fièvre hémorragique de Crimée-Congo</term>
<term>Infections à coronavirus</term>
<term>Protéines virales</term>
<term>Ubiquitine</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Fièvre hémorragique de Crimée-Congo</term>
<term>Infections à coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term>
<term>Hemorrhagic Fever, Crimean</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Drug Evaluation, Preclinical</term>
<term>Humans</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Humains</term>
<term>Protéines virales</term>
<term>Ubiquitinylation</term>
<term>Virus de la fièvre hémorragique de Crimée-Congo</term>
<term>Évaluation préclinique de médicament</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Komander, D" uniqKey="Komander D">D Komander</name>
</author>
<author><name sortKey="Rape, M" uniqKey="Rape M">M Rape</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yau, R" uniqKey="Yau R">R Yau</name>
</author>
<author><name sortKey="Rape, M" uniqKey="Rape M">M Rape</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jiang, X" uniqKey="Jiang X">X Jiang</name>
</author>
<author><name sortKey="Chen, Zj" uniqKey="Chen Z">ZJ Chen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mielech, Am" uniqKey="Mielech A">AM Mielech</name>
</author>
<author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name>
</author>
<author><name sortKey="Mesecar, Ad" uniqKey="Mesecar A">AD Mesecar</name>
</author>
<author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Morales, Dj" uniqKey="Morales D">DJ Morales</name>
</author>
<author><name sortKey="Lenschow, Dj" uniqKey="Lenschow D">DJ Lenschow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chenon, M" uniqKey="Chenon M">M Chenon</name>
</author>
<author><name sortKey="Camborde, L" uniqKey="Camborde L">L Camborde</name>
</author>
<author><name sortKey="Cheminant, S" uniqKey="Cheminant S">S Cheminant</name>
</author>
<author><name sortKey="Jupin, I" uniqKey="Jupin I">I Jupin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Isaacson, Mk" uniqKey="Isaacson M">MK Isaacson</name>
</author>
<author><name sortKey="Ploegh, Hl" uniqKey="Ploegh H">HL Ploegh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name>
</author>
<author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N van Doremalen</name>
</author>
<author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name>
</author>
<author><name sortKey="Munster, Vj" uniqKey="Munster V">VJ Munster</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bailey Elkin, Ba" uniqKey="Bailey Elkin B">BA Bailey-Elkin</name>
</author>
<author><name sortKey="Knaap, Rc" uniqKey="Knaap R">RC Knaap</name>
</author>
<author><name sortKey="Johnson, Gg" uniqKey="Johnson G">GG Johnson</name>
</author>
<author><name sortKey="Dalebout, Tj" uniqKey="Dalebout T">TJ Dalebout</name>
</author>
<author><name sortKey="Ninaber, Dk" uniqKey="Ninaber D">DK Ninaber</name>
</author>
<author><name sortKey="Van Kasteren, Pb" uniqKey="Van Kasteren P">PB van Kasteren</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mielech, Am" uniqKey="Mielech A">AM Mielech</name>
</author>
<author><name sortKey="Kilianski, A" uniqKey="Kilianski A">A Kilianski</name>
</author>
<author><name sortKey="Baez Santos, Ym" uniqKey="Baez Santos Y">YM Baez-Santos</name>
</author>
<author><name sortKey="Mesecar, Ad" uniqKey="Mesecar A">AD Mesecar</name>
</author>
<author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Clementz, Ma" uniqKey="Clementz M">MA Clementz</name>
</author>
<author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name>
</author>
<author><name sortKey="Banach, Bs" uniqKey="Banach B">BS Banach</name>
</author>
<author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name>
</author>
<author><name sortKey="Sun, L" uniqKey="Sun L">L Sun</name>
</author>
<author><name sortKey="Ratia, K" uniqKey="Ratia K">K Ratia</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xing, Y" uniqKey="Xing Y">Y Xing</name>
</author>
<author><name sortKey="Chen, J" uniqKey="Chen J">J Chen</name>
</author>
<author><name sortKey="Tu, J" uniqKey="Tu J">J Tu</name>
</author>
<author><name sortKey="Zhang, B" uniqKey="Zhang B">B Zhang</name>
</author>
<author><name sortKey="Chen, X" uniqKey="Chen X">X Chen</name>
</author>
<author><name sortKey="Shi, H" uniqKey="Shi H">H Shi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Devaraj, Sg" uniqKey="Devaraj S">SG Devaraj</name>
</author>
<author><name sortKey="Wang, N" uniqKey="Wang N">N Wang</name>
</author>
<author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name>
</author>
<author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name>
</author>
<author><name sortKey="Tseng, M" uniqKey="Tseng M">M Tseng</name>
</author>
<author><name sortKey="Barretto, N" uniqKey="Barretto N">N Barretto</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zheng, D" uniqKey="Zheng D">D Zheng</name>
</author>
<author><name sortKey="Chen, G" uniqKey="Chen G">G Chen</name>
</author>
<author><name sortKey="Guo, B" uniqKey="Guo B">B Guo</name>
</author>
<author><name sortKey="Cheng, G" uniqKey="Cheng G">G Cheng</name>
</author>
<author><name sortKey="Tang, H" uniqKey="Tang H">H Tang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Baez Santos, Ym" uniqKey="Baez Santos Y">YM Baez-Santos</name>
</author>
<author><name sortKey="St John, Se" uniqKey="St John S">SE St John</name>
</author>
<author><name sortKey="Mesecar, Ad" uniqKey="Mesecar A">AD Mesecar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hilgenfeld, R" uniqKey="Hilgenfeld R">R Hilgenfeld</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Frias Staheli, N" uniqKey="Frias Staheli N">N Frias-Staheli</name>
</author>
<author><name sortKey="Giannakopoulos, Nv" uniqKey="Giannakopoulos N">NV Giannakopoulos</name>
</author>
<author><name sortKey="Kikkert, M" uniqKey="Kikkert M">M Kikkert</name>
</author>
<author><name sortKey="Taylor, Sl" uniqKey="Taylor S">SL Taylor</name>
</author>
<author><name sortKey="Bridgen, A" uniqKey="Bridgen A">A Bridgen</name>
</author>
<author><name sortKey="Paragas, J" uniqKey="Paragas J">J Paragas</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lei, J" uniqKey="Lei J">J Lei</name>
</author>
<author><name sortKey="Mesters, Jr" uniqKey="Mesters J">JR Mesters</name>
</author>
<author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name>
</author>
<author><name sortKey="Anemuller, S" uniqKey="Anemuller S">S Anemuller</name>
</author>
<author><name sortKey="Ma, Q" uniqKey="Ma Q">Q Ma</name>
</author>
<author><name sortKey="Hilgenfeld, R" uniqKey="Hilgenfeld R">R Hilgenfeld</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ratia, K" uniqKey="Ratia K">K Ratia</name>
</author>
<author><name sortKey="Saikatendu, Ks" uniqKey="Saikatendu K">KS Saikatendu</name>
</author>
<author><name sortKey="Santarsiero, Bd" uniqKey="Santarsiero B">BD Santarsiero</name>
</author>
<author><name sortKey="Barretto, N" uniqKey="Barretto N">N Barretto</name>
</author>
<author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name>
</author>
<author><name sortKey="Stevens, Rc" uniqKey="Stevens R">RC Stevens</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="James, Tw" uniqKey="James T">TW James</name>
</author>
<author><name sortKey="Frias Staheli, N" uniqKey="Frias Staheli N">N Frias-Staheli</name>
</author>
<author><name sortKey="Bacik, Jp" uniqKey="Bacik J">JP Bacik</name>
</author>
<author><name sortKey="Levingston Macleod, Jm" uniqKey="Levingston Macleod J">JM Levingston Macleod</name>
</author>
<author><name sortKey="Khajehpour, M" uniqKey="Khajehpour M">M Khajehpour</name>
</author>
<author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A Garcia-Sastre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Akutsu, M" uniqKey="Akutsu M">M Akutsu</name>
</author>
<author><name sortKey="Ye, Y" uniqKey="Ye Y">Y Ye</name>
</author>
<author><name sortKey="Virdee, S" uniqKey="Virdee S">S Virdee</name>
</author>
<author><name sortKey="Chin, Jw" uniqKey="Chin J">JW Chin</name>
</author>
<author><name sortKey="Komander, D" uniqKey="Komander D">D Komander</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Calistri, A" uniqKey="Calistri A">A Calistri</name>
</author>
<author><name sortKey="Munegato, D" uniqKey="Munegato D">D Munegato</name>
</author>
<author><name sortKey="Carli, I" uniqKey="Carli I">I Carli</name>
</author>
<author><name sortKey="Parolin, C" uniqKey="Parolin C">C Parolin</name>
</author>
<author><name sortKey="Palu, G" uniqKey="Palu G">G Palu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Heideker, J" uniqKey="Heideker J">J Heideker</name>
</author>
<author><name sortKey="Wertz, Ie" uniqKey="Wertz I">IE Wertz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kemp, M" uniqKey="Kemp M">M Kemp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ernst, A" uniqKey="Ernst A">A Ernst</name>
</author>
<author><name sortKey="Avvakumov, G" uniqKey="Avvakumov G">G Avvakumov</name>
</author>
<author><name sortKey="Tong, J" uniqKey="Tong J">J Tong</name>
</author>
<author><name sortKey="Fan, Y" uniqKey="Fan Y">Y Fan</name>
</author>
<author><name sortKey="Zhao, Y" uniqKey="Zhao Y">Y Zhao</name>
</author>
<author><name sortKey="Alberts, P" uniqKey="Alberts P">P Alberts</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zhang, W" uniqKey="Zhang W">W Zhang</name>
</author>
<author><name sortKey="Wu, Kp" uniqKey="Wu K">KP Wu</name>
</author>
<author><name sortKey="Sartori, Ma" uniqKey="Sartori M">MA Sartori</name>
</author>
<author><name sortKey="Kamadurai, Hb" uniqKey="Kamadurai H">HB Kamadurai</name>
</author>
<author><name sortKey="Ordureau, A" uniqKey="Ordureau A">A Ordureau</name>
</author>
<author><name sortKey="Jiang, C" uniqKey="Jiang C">C Jiang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Krissinel, E" uniqKey="Krissinel E">E Krissinel</name>
</author>
<author><name sortKey="Henrick, K" uniqKey="Henrick K">K Henrick</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yang, X" uniqKey="Yang X">X Yang</name>
</author>
<author><name sortKey="Chen, X" uniqKey="Chen X">X Chen</name>
</author>
<author><name sortKey="Bian, G" uniqKey="Bian G">G Bian</name>
</author>
<author><name sortKey="Tu, J" uniqKey="Tu J">J Tu</name>
</author>
<author><name sortKey="Xing, Y" uniqKey="Xing Y">Y Xing</name>
</author>
<author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name>
</author>
<author><name sortKey="Van Den Brand, Jm" uniqKey="Van Den Brand J">JM van den Brand</name>
</author>
<author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name>
</author>
<author><name sortKey="Volz, A" uniqKey="Volz A">A Volz</name>
</author>
<author><name sortKey="Wohlsein, P" uniqKey="Wohlsein P">P Wohlsein</name>
</author>
<author><name sortKey="Smits, Sl" uniqKey="Smits S">SL Smits</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Auger, A" uniqKey="Auger A">A Auger</name>
</author>
<author><name sortKey="Park, M" uniqKey="Park M">M Park</name>
</author>
<author><name sortKey="Nitschke, F" uniqKey="Nitschke F">F Nitschke</name>
</author>
<author><name sortKey="Minassian, Lm" uniqKey="Minassian L">LM Minassian</name>
</author>
<author><name sortKey="Beilhartz, Gl" uniqKey="Beilhartz G">GL Beilhartz</name>
</author>
<author><name sortKey="Minassian, Ba" uniqKey="Minassian B">BA Minassian</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="D Astolfo, Ds" uniqKey="D Astolfo D">DS D'Astolfo</name>
</author>
<author><name sortKey="Pagliero, Rj" uniqKey="Pagliero R">RJ Pagliero</name>
</author>
<author><name sortKey="Pras, A" uniqKey="Pras A">A Pras</name>
</author>
<author><name sortKey="Karthaus, Wr" uniqKey="Karthaus W">WR Karthaus</name>
</author>
<author><name sortKey="Clevers, H" uniqKey="Clevers H">H Clevers</name>
</author>
<author><name sortKey="Prasad, V" uniqKey="Prasad V">V Prasad</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gaj, T" uniqKey="Gaj T">T Gaj</name>
</author>
<author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name>
</author>
<author><name sortKey="Anderson, Ke" uniqKey="Anderson K">KE Anderson</name>
</author>
<author><name sortKey="Sirk, Sj" uniqKey="Sirk S">SJ Sirk</name>
</author>
<author><name sortKey="Barbas, Cf" uniqKey="Barbas C">CF Barbas</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Uppalapati, M" uniqKey="Uppalapati M">M Uppalapati</name>
</author>
<author><name sortKey="Lee, Dj" uniqKey="Lee D">DJ Lee</name>
</author>
<author><name sortKey="Mandal, K" uniqKey="Mandal K">K Mandal</name>
</author>
<author><name sortKey="Li, H" uniqKey="Li H">H Li</name>
</author>
<author><name sortKey="Miranda, Lp" uniqKey="Miranda L">LP Miranda</name>
</author>
<author><name sortKey="Lowitz, J" uniqKey="Lowitz J">J Lowitz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Leung, I" uniqKey="Leung I">I Leung</name>
</author>
<author><name sortKey="Dekel, A" uniqKey="Dekel A">A Dekel</name>
</author>
<author><name sortKey="Shifman, Jm" uniqKey="Shifman J">JM Shifman</name>
</author>
<author><name sortKey="Sidhu, Ss" uniqKey="Sidhu S">SS Sidhu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Arkin, Mr" uniqKey="Arkin M">MR Arkin</name>
</author>
<author><name sortKey="Tang, Y" uniqKey="Tang Y">Y Tang</name>
</author>
<author><name sortKey="Wells, Ja" uniqKey="Wells J">JA Wells</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Inn, Ks" uniqKey="Inn K">KS Inn</name>
</author>
<author><name sortKey="Lee, Sh" uniqKey="Lee S">SH Lee</name>
</author>
<author><name sortKey="Rathbun, Jy" uniqKey="Rathbun J">JY Rathbun</name>
</author>
<author><name sortKey="Wong, Ly" uniqKey="Wong L">LY Wong</name>
</author>
<author><name sortKey="Toth, Z" uniqKey="Toth Z">Z Toth</name>
</author>
<author><name sortKey="Machida, K" uniqKey="Machida K">K Machida</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wang, S" uniqKey="Wang S">S Wang</name>
</author>
<author><name sortKey="Wang, K" uniqKey="Wang K">K Wang</name>
</author>
<author><name sortKey="Li, J" uniqKey="Li J">J Li</name>
</author>
<author><name sortKey="Zheng, C" uniqKey="Zheng C">C Zheng</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barretto, N" uniqKey="Barretto N">N Barretto</name>
</author>
<author><name sortKey="Jukneliene, D" uniqKey="Jukneliene D">D Jukneliene</name>
</author>
<author><name sortKey="Ratia, K" uniqKey="Ratia K">K Ratia</name>
</author>
<author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name>
</author>
<author><name sortKey="Mesecar, Ad" uniqKey="Mesecar A">AD Mesecar</name>
</author>
<author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name>
</author>
<author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name>
</author>
<author><name sortKey="Ratia, K" uniqKey="Ratia K">K Ratia</name>
</author>
<author><name sortKey="Mesecar, Ad" uniqKey="Mesecar A">AD Mesecar</name>
</author>
<author><name sortKey="Wilkinson, Kd" uniqKey="Wilkinson K">KD Wilkinson</name>
</author>
<author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lindner, Ha" uniqKey="Lindner H">HA Lindner</name>
</author>
<author><name sortKey="Fotouhi Ardakani, N" uniqKey="Fotouhi Ardakani N">N Fotouhi-Ardakani</name>
</author>
<author><name sortKey="Lytvyn, V" uniqKey="Lytvyn V">V Lytvyn</name>
</author>
<author><name sortKey="Lachance, P" uniqKey="Lachance P">P Lachance</name>
</author>
<author><name sortKey="Sulea, T" uniqKey="Sulea T">T Sulea</name>
</author>
<author><name sortKey="Menard, R" uniqKey="Menard R">R Menard</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ziebuhr, J" uniqKey="Ziebuhr J">J Ziebuhr</name>
</author>
<author><name sortKey="Schelle, B" uniqKey="Schelle B">B Schelle</name>
</author>
<author><name sortKey="Karl, N" uniqKey="Karl N">N Karl</name>
</author>
<author><name sortKey="Minskaia, E" uniqKey="Minskaia E">E Minskaia</name>
</author>
<author><name sortKey="Bayer, S" uniqKey="Bayer S">S Bayer</name>
</author>
<author><name sortKey="Siddell, Sg" uniqKey="Siddell S">SG Siddell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bergeron, E" uniqKey="Bergeron E">E Bergeron</name>
</author>
<author><name sortKey="Albarino, Cg" uniqKey="Albarino C">CG Albarino</name>
</author>
<author><name sortKey="Khristova, Ml" uniqKey="Khristova M">ML Khristova</name>
</author>
<author><name sortKey="Nichol, St" uniqKey="Nichol S">ST Nichol</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lombardi, C" uniqKey="Lombardi C">C Lombardi</name>
</author>
<author><name sortKey="Ayach, M" uniqKey="Ayach M">M Ayach</name>
</author>
<author><name sortKey="Beaurepaire, L" uniqKey="Beaurepaire L">L Beaurepaire</name>
</author>
<author><name sortKey="Chenon, M" uniqKey="Chenon M">M Chenon</name>
</author>
<author><name sortKey="Andreani, J" uniqKey="Andreani J">J Andreani</name>
</author>
<author><name sortKey="Guerois, R" uniqKey="Guerois R">R Guerois</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Miao, X" uniqKey="Miao X">X Miao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Agrawal, As" uniqKey="Agrawal A">AS Agrawal</name>
</author>
<author><name sortKey="Garron, T" uniqKey="Garron T">T Garron</name>
</author>
<author><name sortKey="Tao, X" uniqKey="Tao X">X Tao</name>
</author>
<author><name sortKey="Peng, Bh" uniqKey="Peng B">BH Peng</name>
</author>
<author><name sortKey="Wakamiya, M" uniqKey="Wakamiya M">M Wakamiya</name>
</author>
<author><name sortKey="Chan, Ts" uniqKey="Chan T">TS Chan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pascal, Ke" uniqKey="Pascal K">KE Pascal</name>
</author>
<author><name sortKey="Coleman, Cm" uniqKey="Coleman C">CM Coleman</name>
</author>
<author><name sortKey="Mujica, Ao" uniqKey="Mujica A">AO Mujica</name>
</author>
<author><name sortKey="Kamat, V" uniqKey="Kamat V">V Kamat</name>
</author>
<author><name sortKey="Badithe, A" uniqKey="Badithe A">A Badithe</name>
</author>
<author><name sortKey="Fairhurst, J" uniqKey="Fairhurst J">J Fairhurst</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name>
</author>
<author><name sortKey="Li, K" uniqKey="Li K">K Li</name>
</author>
<author><name sortKey="Wohlford Lenane, C" uniqKey="Wohlford Lenane C">C Wohlford-Lenane</name>
</author>
<author><name sortKey="Agnihothram, Ss" uniqKey="Agnihothram S">SS Agnihothram</name>
</author>
<author><name sortKey="Fett, C" uniqKey="Fett C">C Fett</name>
</author>
<author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, K" uniqKey="Li K">K Li</name>
</author>
<author><name sortKey="Wohlford Lenane, C" uniqKey="Wohlford Lenane C">C Wohlford-Lenane</name>
</author>
<author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name>
</author>
<author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name>
</author>
<author><name sortKey="Jewell, Ak" uniqKey="Jewell A">AK Jewell</name>
</author>
<author><name sortKey="Reznikov, Lr" uniqKey="Reznikov L">LR Reznikov</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, K" uniqKey="Li K">K Li</name>
</author>
<author><name sortKey="Wohlford Lenane, Cl" uniqKey="Wohlford Lenane C">CL Wohlford-Lenane</name>
</author>
<author><name sortKey="Channappanavar, R" uniqKey="Channappanavar R">R Channappanavar</name>
</author>
<author><name sortKey="Park, Je" uniqKey="Park J">JE Park</name>
</author>
<author><name sortKey="Earnest, Jt" uniqKey="Earnest J">JT Earnest</name>
</author>
<author><name sortKey="Bair, Tb" uniqKey="Bair T">TB Bair</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N van Doremalen</name>
</author>
<author><name sortKey="Munster, Vj" uniqKey="Munster V">VJ Munster</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cockrell, As" uniqKey="Cockrell A">AS Cockrell</name>
</author>
<author><name sortKey="Yount, Bl" uniqKey="Yount B">BL Yount</name>
</author>
<author><name sortKey="Scobey, T" uniqKey="Scobey T">T Scobey</name>
</author>
<author><name sortKey="Jensen, K" uniqKey="Jensen K">K Jensen</name>
</author>
<author><name sortKey="Douglas, M" uniqKey="Douglas M">M Douglas</name>
</author>
<author><name sortKey="Beall, A" uniqKey="Beall A">A Beall</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lee, H" uniqKey="Lee H">H Lee</name>
</author>
<author><name sortKey="Lei, H" uniqKey="Lei H">H Lei</name>
</author>
<author><name sortKey="Santarsiero, Bd" uniqKey="Santarsiero B">BD Santarsiero</name>
</author>
<author><name sortKey="Gatuz, Jl" uniqKey="Gatuz J">JL Gatuz</name>
</author>
<author><name sortKey="Cao, S" uniqKey="Cao S">S Cao</name>
</author>
<author><name sortKey="Rice, Aj" uniqKey="Rice A">AJ Rice</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Van Kasteren, Pb" uniqKey="Van Kasteren P">PB van Kasteren</name>
</author>
<author><name sortKey="Bailey Elkin, Ba" uniqKey="Bailey Elkin B">BA Bailey-Elkin</name>
</author>
<author><name sortKey="James, Tw" uniqKey="James T">TW James</name>
</author>
<author><name sortKey="Ninaber, Dk" uniqKey="Ninaber D">DK Ninaber</name>
</author>
<author><name sortKey="Beugeling, C" uniqKey="Beugeling C">C Beugeling</name>
</author>
<author><name sortKey="Khajehpour, M" uniqKey="Khajehpour M">M Khajehpour</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Deng, X" uniqKey="Deng X">X Deng</name>
</author>
<author><name sortKey="Stjohn, Se" uniqKey="Stjohn S">SE StJohn</name>
</author>
<author><name sortKey="Osswald, Hl" uniqKey="Osswald H">HL Osswald</name>
</author>
<author><name sortKey="O Brien, A" uniqKey="O Brien A">A O'Brien</name>
</author>
<author><name sortKey="Banach, Bs" uniqKey="Banach B">BS Banach</name>
</author>
<author><name sortKey="Sleeman, K" uniqKey="Sleeman K">K Sleeman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tonikian, R" uniqKey="Tonikian R">R Tonikian</name>
</author>
<author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y Zhang</name>
</author>
<author><name sortKey="Boone, C" uniqKey="Boone C">C Boone</name>
</author>
<author><name sortKey="Sidhu, Ss" uniqKey="Sidhu S">SS Sidhu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="D Arcy, A" uniqKey="D Arcy A">A D'Arcy</name>
</author>
<author><name sortKey="Villard, F" uniqKey="Villard F">F Villard</name>
</author>
<author><name sortKey="Marsh, M" uniqKey="Marsh M">M Marsh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ireton, Gc" uniqKey="Ireton G">GC Ireton</name>
</author>
<author><name sortKey="Stoddard, Bl" uniqKey="Stoddard B">BL Stoddard</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Georgieva, Dg" uniqKey="Georgieva D">DG Georgieva</name>
</author>
<author><name sortKey="Kuil, Me" uniqKey="Kuil M">ME Kuil</name>
</author>
<author><name sortKey="Oosterkamp, Th" uniqKey="Oosterkamp T">TH Oosterkamp</name>
</author>
<author><name sortKey="Zandbergen, Hw" uniqKey="Zandbergen H">HW Zandbergen</name>
</author>
<author><name sortKey="Abrahams, Jp" uniqKey="Abrahams J">JP Abrahams</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Carlotti, F" uniqKey="Carlotti F">F Carlotti</name>
</author>
<author><name sortKey="Bazuine, M" uniqKey="Bazuine M">M Bazuine</name>
</author>
<author><name sortKey="Kekarainen, T" uniqKey="Kekarainen T">T Kekarainen</name>
</author>
<author><name sortKey="Seppen, J" uniqKey="Seppen J">J Seppen</name>
</author>
<author><name sortKey="Pognonec, P" uniqKey="Pognonec P">P Pognonec</name>
</author>
<author><name sortKey="Maassen, Ja" uniqKey="Maassen J">JA Maassen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Van Den Worm, Sh" uniqKey="Van Den Worm S">SH van den Worm</name>
</author>
<author><name sortKey="Eriksson, Kk" uniqKey="Eriksson K">KK Eriksson</name>
</author>
<author><name sortKey="Zevenhoven, Jc" uniqKey="Zevenhoven J">JC Zevenhoven</name>
</author>
<author><name sortKey="Weber, F" uniqKey="Weber F">F Weber</name>
</author>
<author><name sortKey="Zust, R" uniqKey="Zust R">R Zust</name>
</author>
<author><name sortKey="Kuri, T" uniqKey="Kuri T">T Kuri</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Chou, Cy" uniqKey="Chou C">CY Chou</name>
</author>
<author><name sortKey="Lai, Hy" uniqKey="Lai H">HY Lai</name>
</author>
<author><name sortKey="Chen, Hy" uniqKey="Chen H">HY Chen</name>
</author>
<author><name sortKey="Cheng, Sc" uniqKey="Cheng S">SC Cheng</name>
</author>
<author><name sortKey="Cheng, Kw" uniqKey="Cheng K">KW Cheng</name>
</author>
<author><name sortKey="Chou, Yw" uniqKey="Chou Y">YW Chou</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<affiliations><list><country><li>Canada</li>
<li>Pays-Bas</li>
</country>
<region><li>Hollande-Méridionale</li>
<li>Manitoba</li>
<li>Ontario</li>
</region>
<settlement><li>Leyde</li>
<li>Toronto</li>
<li>Winnipeg</li>
</settlement>
<orgName><li>Université de Toronto</li>
<li>Université du Manitoba</li>
</orgName>
</list>
<tree><country name="Canada"><region name="Ontario"><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name>
</region>
<name sortKey="Bailey Elkin, Ben A" sort="Bailey Elkin, Ben A" uniqKey="Bailey Elkin B" first="Ben A." last="Bailey-Elkin">Ben A. Bailey-Elkin</name>
<name sortKey="Gu, Jun" sort="Gu, Jun" uniqKey="Gu J" first="Jun" last="Gu">Jun Gu</name>
<name sortKey="He, Wenguang" sort="He, Wenguang" uniqKey="He W" first="Wenguang" last="He">Wenguang He</name>
<name sortKey="Johnson, Garrett G" sort="Johnson, Garrett G" uniqKey="Johnson G" first="Garrett G." last="Johnson">Garrett G. Johnson</name>
<name sortKey="Khare, Baldeep" sort="Khare, Baldeep" uniqKey="Khare B" first="Baldeep" last="Khare">Baldeep Khare</name>
<name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L." last="Mark">Brian L. Mark</name>
<name sortKey="Mcleish, Nigel J" sort="Mcleish, Nigel J" uniqKey="Mcleish N" first="Nigel J." last="Mcleish">Nigel J. Mcleish</name>
<name sortKey="Sidhu, Sachdev S" sort="Sidhu, Sachdev S" uniqKey="Sidhu S" first="Sachdev S." last="Sidhu">Sachdev S. Sidhu</name>
</country>
<country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Knaap, Robert C M" sort="Knaap, Robert C M" uniqKey="Knaap R" first="Robert C. M." last="Knaap">Robert C. M. Knaap</name>
</region>
<name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J." last="Dalebout">Tim J. Dalebout</name>
<name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name>
<name sortKey="Van Kasteren, Puck B" sort="Van Kasteren, Puck B" uniqKey="Van Kasteren P" first="Puck B." last="Van Kasteren">Puck B. Van Kasteren</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000C31 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000C31 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= MersV1 |flux= Main |étape= Exploration |type= RBID |clé= PMC:5451084 |texte= Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:28542609" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a MersV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |