Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection.
Identifieur interne : 001556 ( PubMed/Curation ); précédent : 001555; suivant : 001557Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection.
Auteurs : Rudragouda Channappanavar [États-Unis] ; Lu Lu [République populaire de Chine] ; Shuai Xia [République populaire de Chine] ; Lanying Du [États-Unis] ; David K. Meyerholz [États-Unis] ; Stanley Perlman [États-Unis] ; Shibo Jiang [États-Unis]Source :
- The Journal of infectious diseases [ 1537-6613 ] ; 2015.
Descripteurs français
- KwdFr :
- Administration par voie nasale, Animaux, Antiviraux (administration et posologie), Charge virale, Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Humains, Infections à coronavirus (), Lignée cellulaire, Modèles animaux de maladie humaine, Peptides (administration et posologie), Poumon (virologie), Pénétration virale (), Souris de lignée C57BL.
- MESH :
- administration et posologie : Antiviraux, Peptides.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- virologie : Poumon.
- Administration par voie nasale, Animaux, Charge virale, Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Infections à coronavirus, Lignée cellulaire, Modèles animaux de maladie humaine, Pénétration virale, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Administration, Intranasal, Animals, Antiviral Agents (administration & dosage), Cell Line, Coronavirus Infections (prevention & control), Disease Models, Animal, Humans, Lung (virology), Mice, Inbred C57BL, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), Peptides (administration & dosage), Viral Load, Virus Internalization (drug effects).
- MESH :
- chemical , administration & dosage : Antiviral Agents, Peptides.
- drug effects : Middle East Respiratory Syndrome Coronavirus, Virus Internalization.
- physiology : Middle East Respiratory Syndrome Coronavirus.
- prevention & control : Coronavirus Infections.
- virology : Lung.
- Administration, Intranasal, Animals, Cell Line, Disease Models, Animal, Humans, Mice, Inbred C57BL, Viral Load.
Abstract
To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein-mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein-mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5-human dipeptidyl peptidase 4-transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV-infected patients.
DOI: 10.1093/infdis/jiv325
PubMed: 26164863
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Meyerholz</name><affiliation wicri:level="4"><nlm:affiliation>Pathology, University of Iowa, Iowa City.</nlm:affiliation><orgName type="university">Université de l'Iowa</orgName><country>États-Unis</country><placeName><settlement type="city">Iowa City</settlement><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="4"><nlm:affiliation>Departments of Microbiology, University of Iowa, Iowa City Pediatrics, University of Iowa, Iowa City.</nlm:affiliation><orgName type="university">Université de l'Iowa</orgName><country>États-Unis</country><placeName><settlement type="city">Iowa City</settlement><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation wicri:level="2"><nlm:affiliation>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China Lindsley F. 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Kimball Research Institute, New York Blood Center</wicri:cityArea></affiliation></author></analytic><series><title level="j">The Journal of infectious diseases</title><idno type="eISSN">1537-6613</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Administration, Intranasal</term><term>Animals</term><term>Antiviral Agents (administration & dosage)</term><term>Cell Line</term><term>Coronavirus Infections (prevention & control)</term><term>Disease Models, Animal</term><term>Humans</term><term>Lung (virology)</term><term>Mice, Inbred C57BL</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>Peptides (administration & dosage)</term><term>Viral Load</term><term>Virus Internalization (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Administration par voie nasale</term><term>Animaux</term><term>Antiviraux (administration et posologie)</term><term>Charge virale</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Humains</term><term>Infections à coronavirus ()</term><term>Lignée cellulaire</term><term>Modèles animaux de maladie humaine</term><term>Peptides (administration et posologie)</term><term>Poumon (virologie)</term><term>Pénétration virale ()</term><term>Souris de lignée C57BL</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antiviral Agents</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Antiviraux</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Administration, Intranasal</term><term>Animals</term><term>Cell Line</term><term>Disease Models, Animal</term><term>Humans</term><term>Mice, Inbred C57BL</term><term>Viral Load</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Administration par voie nasale</term><term>Animaux</term><term>Charge virale</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Humains</term><term>Infections à coronavirus</term><term>Lignée cellulaire</term><term>Modèles animaux de maladie humaine</term><term>Pénétration virale</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein-mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein-mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5-human dipeptidyl peptidase 4-transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV-infected patients. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26164863</PMID><DateCompleted><Year>2016</Year><Month>03</Month><Day>08</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1537-6613</ISSN><JournalIssue CitedMedium="Internet"><Volume>212</Volume><Issue>12</Issue><PubDate><Year>2015</Year><Month>Dec</Month><Day>15</Day></PubDate></JournalIssue><Title>The Journal of infectious diseases</Title><ISOAbbreviation>J. Infect. Dis.</ISOAbbreviation></Journal><ArticleTitle>Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection.</ArticleTitle><Pagination><MedlinePgn>1894-903</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/infdis/jiv325</ELocationID><Abstract><AbstractText>To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein-mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein-mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5-human dipeptidyl peptidase 4-transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV-infected patients. </AbstractText><CopyrightInformation>© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Channappanavar</LastName><ForeName>Rudragouda</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Departments of Microbiology, University of Iowa, Iowa City.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Lu</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xia</LastName><ForeName>Shuai</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Du</LastName><ForeName>Lanying</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Meyerholz</LastName><ForeName>David K</ForeName><Initials>DK</Initials><AffiliationInfo><Affiliation>Pathology, University of Iowa, Iowa City.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Perlman</LastName><ForeName>Stanley</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Departments of Microbiology, University of Iowa, Iowa City Pediatrics, University of Iowa, Iowa City.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jiang</LastName><ForeName>Shibo</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China Lindsley F. Kimball Research Institute, New York Blood Center, New York.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P01AI60699</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI091322</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P01 AI060699</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01AI091322</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 DK054759</GrantID><Acronym>DK</Acronym><Agency>NIDDK 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>2015</Year><Month>06</Month><Day>08</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Infect Dis</MedlineTA><NlmUniqueID>0413675</NlmUniqueID><ISSNLinking>0022-1899</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010455">Peptides</NameOfSubstance></Chemical></ChemicalList><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000281" MajorTopicYN="N">Administration, Intranasal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019562" MajorTopicYN="N">Viral Load</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053586" MajorTopicYN="N">Virus Internalization</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">MERS-CoV</Keyword><Keyword MajorTopicYN="N">fusion inhibitor</Keyword><Keyword MajorTopicYN="N">interferon</Keyword><Keyword 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