Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection
Identifieur interne : 001611 ( Main/Exploration ); précédent : 001610; suivant : 001612Protective 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 [République populaire de Chine, États-Unis]Source :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 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.
Url:
DOI: 10.1093/infdis/jiv325
PubMed: 26164863
PubMed Central: 4655857
Affiliations:
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Kimball Research Institute, New York Blood Center, New York</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea></affiliation></author><author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name><affiliation wicri:level="4"><nlm:aff id="af2">Pathology, University of Iowa, Iowa City</nlm:aff><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:aff id="af1">Departments of Microbiology, University of Iowa, Iowa City</nlm:aff><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><affiliation wicri:level="4"><nlm:aff id="af3">Pediatrics, University of Iowa, Iowa City</nlm:aff><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="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea><wicri:noRegion>Fudan University</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="af5">Lindsley F. Kimball Research Institute, New York Blood Center, New York</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea></affiliation></author></analytic><series><title level="j">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><date when="2015">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"><title>Abstract</title><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Adme" uniqKey="Osterhaus A">ADME Osterhaus</name></author><author><name sortKey="Fouchier, Ram" uniqKey="Fouchier R">RAM Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A Assiri</name></author><author><name sortKey="Mcgeer, A" uniqKey="Mcgeer A">A McGeer</name></author><author><name sortKey="Perl, Tm" uniqKey="Perl T">TM 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de New York</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Iowa"><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name></region><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name></noRegion><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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