Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors
Identifieur interne : 000718 ( Ncbi/Curation ); précédent : 000717; suivant : 000719Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors
Auteurs : Shuwen Liu [États-Unis] ; Gengfu Xiao [République populaire de Chine] ; Yibang Chen [États-Unis] ; Yuxian He [États-Unis] ; Jinkui Niu [États-Unis] ; Carlos R. Escalante [États-Unis] ; Huabao Xiong [États-Unis] ; James Farmar [États-Unis] ; Asim K. Debnath [États-Unis] ; Po Tien [République populaire de Chine] ; Shibo Jiang [États-Unis]Source :
- Lancet (London, England) [ 0140-6736 ] ; 2004.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Cellules cultivées, Chromatographie en phase liquide à haute performance, Conformation des protéines (), Dichroïsme circulaire, Fractionnement chimique, Fusion membranaire (), Fusion membranaire (physiologie), Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (), Glycoprotéines membranaires (métabolisme), Glycoprotéines membranaires (pharmacologie), Humains, Oligopeptides (), Oligopeptides (métabolisme), Protéine d'enveloppe gp41 du VIH (), Protéine d'enveloppe gp41 du VIH (métabolisme), Protéine d'enveloppe gp41 du VIH (pharmacologie), Protéines de fusion virale (), Protéines de fusion virale (métabolisme), Protéines de l'enveloppe virale (), Protéines de l'enveloppe virale (métabolisme), Protéines de l'enveloppe virale (pharmacologie), Résonance plasmonique de surface, Similitude de séquences d'acides nucléiques, Syndrome respiratoire aigu sévère (), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (traitement médicamenteux), Virus du SRAS (), Virus du SRAS (métabolisme), Électrophorèse sur gel de polyacrylamide.
- MESH :
- métabolisme : Glycoprotéines membranaires, Oligopeptides, Protéine d'enveloppe gp41 du VIH, Protéines de fusion virale, Protéines de l'enveloppe virale, Syndrome respiratoire aigu sévère, Virus du SRAS.
- pharmacologie : Agents antiVIH, Glycoprotéines membranaires, Protéine d'enveloppe gp41 du VIH, Protéines de l'enveloppe virale.
- physiologie : Fusion membranaire.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- Agents antiVIH, Cellules cultivées, Chromatographie en phase liquide à haute performance, Conformation des protéines, Dichroïsme circulaire, Fractionnement chimique, Fusion membranaire, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires, Humains, Oligopeptides, Protéine d'enveloppe gp41 du VIH, Protéines de fusion virale, Protéines de l'enveloppe virale, Résonance plasmonique de surface, Similitude de séquences d'acides nucléiques, Syndrome respiratoire aigu sévère, Virus du SRAS, Électrophorèse sur gel de polyacrylamide.
English descriptors
- KwdEn :
- Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Cells, Cultured, Chemical Fractionation, Chromatography, High Pressure Liquid, Circular Dichroism, Electrophoresis, Polyacrylamide Gel, HIV Envelope Protein gp41 (chemistry), HIV Envelope Protein gp41 (drug effects), HIV Envelope Protein gp41 (metabolism), HIV Envelope Protein gp41 (pharmacology), Humans, Membrane Fusion (drug effects), Membrane Fusion (physiology), Membrane Glycoproteins (chemistry), Membrane Glycoproteins (metabolism), Membrane Glycoproteins (pharmacology), Oligopeptides (chemistry), Oligopeptides (drug effects), Oligopeptides (metabolism), Protein Conformation (drug effects), SARS Virus (chemistry), SARS Virus (drug effects), SARS Virus (metabolism), Sequence Homology, Nucleic Acid, Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (prevention & control), Spike Glycoprotein, Coronavirus, Surface Plasmon Resonance, Viral Envelope Proteins (chemistry), Viral Envelope Proteins (metabolism), Viral Envelope Proteins (pharmacology), Viral Fusion Proteins (chemistry), Viral Fusion Proteins (metabolism).
- MESH :
- chemical , chemistry : Anti-HIV Agents, HIV Envelope Protein gp41, Membrane Glycoproteins, Oligopeptides, Viral Envelope Proteins, Viral Fusion Proteins.
- chemical , drug effects : HIV Envelope Protein gp41, Oligopeptides.
- chemical , metabolism : HIV Envelope Protein gp41, Membrane Glycoproteins, Oligopeptides, Viral Envelope Proteins, Viral Fusion Proteins.
- chemical , pharmacology : Anti-HIV Agents, HIV Envelope Protein gp41, Membrane Glycoproteins, Viral Envelope Proteins.
- chemistry : SARS Virus.
- drug effects : Membrane Fusion, Protein Conformation, SARS Virus.
- drug therapy : Severe Acute Respiratory Syndrome.
- metabolism : SARS Virus, Severe Acute Respiratory Syndrome.
- physiology : Membrane Fusion.
- prevention & control : Severe Acute Respiratory Syndrome.
- Cells, Cultured, Chemical Fractionation, Chromatography, High Pressure Liquid, Circular Dichroism, Electrophoresis, Polyacrylamide Gel, Humans, Sequence Homology, Nucleic Acid, Spike Glycoprotein, Coronavirus, Surface Plasmon Resonance.
Abstract
Studies on the fusion-inhibitory peptides derived from the heptad repeat 1 and 2 (HR1 and HR2) regions of the HIV-1 envelope glycoprotein gp41 provided crucial information on the viral fusogenic mechanism. We used a similar approach to study the fusogenic mechanism of severe-acute-respiratory-syndrome-associated coronavirus (SARS-CoV).
We tested the inhibitory activity against infection of two sets of peptides corresponding to sequences of SARS-CoV spike protein HR1 and HR2 regions and investigated the interactions between the HR1 and HR2 peptides by surface plasmon resonance, sedimentation equilibration analysis, circular dichroism, native polyacrylamide-gel electrophoresis, size exclusion high-performance liquid chromatography, and computer-aided homology modelling and molecule docking analysis.
One peptide, CP-1, derived from the HR2 region, inhibited SARS-CoV infection in the micromolar range. CP-1 bound with high affinity to a peptide from the HR1 region, NP-1. CP-1 alone had low -helicity and self-associated to form a trimer in phosphate buffer (pH 7·2). CP-1 and NP-1 mixed in equimolar concentrations formed a six-helix bundle, similar to the fusogenic core structure of HIV-1 gp41.
After binding to the target cell, the transmembrane spike protein might change conformation by association between the HR1 and HR2 regions to form an oligomeric structure, leading to fusion between the viral and target-cell membranes. At the prefusion intermediate state, CP-1 could bind to the HR1 region and interfere with the conformational changes, resulting in inhibition of SARS-CoV fusion with the target cells. CP-1 might be modifiable to increase its anti-SARS-CoV activity and could be further developed as an antiviral agent for treatment or prophylaxis of SARS-CoV infection.
Url:
DOI: 10.1016/S0140-6736(04)15788-7
PubMed: 15043961
PubMed Central: 7140173
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PMC:7140173Le document en format XML
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Blood Center, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Niu, Jinkui" sort="Niu, Jinkui" uniqKey="Niu J" first="Jinkui" last="Niu">Jinkui Niu</name><affiliation wicri:level="2"><nlm:aff id="aff3">Mount Sinai School of Medicine, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Mount Sinai School of Medicine, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Escalante, Carlos R" sort="Escalante, Carlos R" uniqKey="Escalante C" first="Carlos R" last="Escalante">Carlos R. Escalante</name><affiliation wicri:level="2"><nlm:aff id="aff3">Mount Sinai School of Medicine, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Mount Sinai School of Medicine, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Xiong, Huabao" sort="Xiong, Huabao" uniqKey="Xiong H" first="Huabao" last="Xiong">Huabao Xiong</name><affiliation wicri:level="2"><nlm:aff id="aff3">Mount Sinai School of Medicine, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Mount Sinai School of Medicine, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Farmar, James" sort="Farmar, James" uniqKey="Farmar J" first="James" last="Farmar">James Farmar</name><affiliation wicri:level="2"><nlm:aff id="aff1">Lindsley F Kimball Research Institute, New York Blood Center, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F Kimball Research Institute, New York Blood Center, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Debnath, Asim K" sort="Debnath, Asim K" uniqKey="Debnath A" first="Asim K" last="Debnath">Asim K. Debnath</name><affiliation wicri:level="2"><nlm:aff id="aff1">Lindsley F Kimball Research Institute, New York Blood Center, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F Kimball Research Institute, New York Blood Center, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Tien, Po" sort="Tien, Po" uniqKey="Tien P" first="Po" last="Tien">Po Tien</name><affiliation wicri:level="4"><nlm:aff id="aff2">Modern Virology Research Center, Wuhan University, Wuhan, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Modern Virology Research Center, Wuhan University, Wuhan</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName><orgName type="university">Université de Wuhan</orgName></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:aff id="aff1">Lindsley F Kimball Research Institute, New York Blood Center, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F Kimball Research Institute, New York Blood Center, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j">Lancet (London, England)</title><idno type="ISSN">0140-6736</idno><idno type="eISSN">1474-547X</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (chemistry)</term><term>Anti-HIV Agents (pharmacology)</term><term>Cells, Cultured</term><term>Chemical Fractionation</term><term>Chromatography, High Pressure Liquid</term><term>Circular Dichroism</term><term>Electrophoresis, Polyacrylamide Gel</term><term>HIV Envelope Protein gp41 (chemistry)</term><term>HIV Envelope Protein gp41 (drug effects)</term><term>HIV Envelope Protein gp41 (metabolism)</term><term>HIV Envelope Protein gp41 (pharmacology)</term><term>Humans</term><term>Membrane Fusion (drug effects)</term><term>Membrane Fusion (physiology)</term><term>Membrane Glycoproteins (chemistry)</term><term>Membrane Glycoproteins (metabolism)</term><term>Membrane Glycoproteins (pharmacology)</term><term>Oligopeptides (chemistry)</term><term>Oligopeptides (drug effects)</term><term>Oligopeptides (metabolism)</term><term>Protein Conformation (drug effects)</term><term>SARS Virus (chemistry)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (metabolism)</term><term>Sequence Homology, Nucleic Acid</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (metabolism)</term><term>Severe Acute Respiratory Syndrome (prevention & control)</term><term>Spike Glycoprotein, Coronavirus</term><term>Surface Plasmon Resonance</term><term>Viral Envelope Proteins (chemistry)</term><term>Viral Envelope Proteins (metabolism)</term><term>Viral Envelope Proteins (pharmacology)</term><term>Viral Fusion Proteins (chemistry)</term><term>Viral Fusion Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Cellules cultivées</term><term>Chromatographie en phase liquide à haute performance</term><term>Conformation des protéines ()</term><term>Dichroïsme circulaire</term><term>Fractionnement chimique</term><term>Fusion membranaire ()</term><term>Fusion membranaire (physiologie)</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires ()</term><term>Glycoprotéines membranaires (métabolisme)</term><term>Glycoprotéines membranaires (pharmacologie)</term><term>Humains</term><term>Oligopeptides ()</term><term>Oligopeptides (métabolisme)</term><term>Protéine d'enveloppe gp41 du VIH ()</term><term>Protéine d'enveloppe gp41 du VIH (métabolisme)</term><term>Protéine d'enveloppe gp41 du VIH (pharmacologie)</term><term>Protéines de fusion virale ()</term><term>Protéines de fusion virale (métabolisme)</term><term>Protéines de l'enveloppe virale ()</term><term>Protéines de l'enveloppe virale (métabolisme)</term><term>Protéines de l'enveloppe virale (pharmacologie)</term><term>Résonance plasmonique de surface</term><term>Similitude de séquences d'acides nucléiques</term><term>Syndrome respiratoire aigu sévère ()</term><term>Syndrome respiratoire aigu sévère (métabolisme)</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Virus du SRAS ()</term><term>Virus du SRAS (métabolisme)</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>HIV Envelope Protein gp41</term><term>Membrane Glycoproteins</term><term>Oligopeptides</term><term>Viral Envelope Proteins</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>HIV Envelope Protein gp41</term><term>Oligopeptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Envelope Protein gp41</term><term>Membrane Glycoproteins</term><term>Oligopeptides</term><term>Viral Envelope Proteins</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>HIV Envelope Protein gp41</term><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Membrane Fusion</term><term>Protein Conformation</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéines membranaires</term><term>Oligopeptides</term><term>Protéine d'enveloppe gp41 du VIH</term><term>Protéines de fusion virale</term><term>Protéines de l'enveloppe virale</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term><term>Glycoprotéines membranaires</term><term>Protéine d'enveloppe gp41 du VIH</term><term>Protéines de l'enveloppe virale</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Fusion membranaire</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Membrane Fusion</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cells, Cultured</term><term>Chemical Fractionation</term><term>Chromatography, High Pressure Liquid</term><term>Circular Dichroism</term><term>Electrophoresis, Polyacrylamide Gel</term><term>Humans</term><term>Sequence Homology, Nucleic Acid</term><term>Spike Glycoprotein, Coronavirus</term><term>Surface Plasmon Resonance</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Cellules cultivées</term><term>Chromatographie en phase liquide à haute performance</term><term>Conformation des protéines</term><term>Dichroïsme circulaire</term><term>Fractionnement chimique</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires</term><term>Humains</term><term>Oligopeptides</term><term>Protéine d'enveloppe gp41 du VIH</term><term>Protéines de fusion virale</term><term>Protéines de l'enveloppe virale</term><term>Résonance plasmonique de surface</term><term>Similitude de séquences d'acides nucléiques</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec><title>Background</title><p>Studies on the fusion-inhibitory peptides derived from the heptad repeat 1 and 2 (HR1 and HR2) regions of the HIV-1 envelope glycoprotein gp41 provided crucial information on the viral fusogenic mechanism. We used a similar approach to study the fusogenic mechanism of severe-acute-respiratory-syndrome-associated coronavirus (SARS-CoV).</p></sec><sec><title>Methods</title><p>We tested the inhibitory activity against infection of two sets of peptides corresponding to sequences of SARS-CoV spike protein HR1 and HR2 regions and investigated the interactions between the HR1 and HR2 peptides by surface plasmon resonance, sedimentation equilibration analysis, circular dichroism, native polyacrylamide-gel electrophoresis, size exclusion high-performance liquid chromatography, and computer-aided homology modelling and molecule docking analysis.</p></sec><sec><title>Findings</title><p>One peptide, CP-1, derived from the HR2 region, inhibited SARS-CoV infection in the micromolar range. CP-1 bound with high affinity to a peptide from the HR1 region, NP-1. CP-1 alone had low -helicity and self-associated to form a trimer in phosphate buffer (pH 7·2). CP-1 and NP-1 mixed in equimolar concentrations formed a six-helix bundle, similar to the fusogenic core structure of HIV-1 gp41.</p></sec><sec><title>Interpretation</title><p>After binding to the target cell, the transmembrane spike protein might change conformation by association between the HR1 and HR2 regions to form an oligomeric structure, leading to fusion between the viral and target-cell membranes. At the prefusion intermediate state, CP-1 could bind to the HR1 region and interfere with the conformational changes, resulting in inhibition of SARS-CoV fusion with the target cells. CP-1 might be modifiable to increase its anti-SARS-CoV activity and could be further developed as an antiviral agent for treatment or prophylaxis of SARS-CoV infection.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Who" uniqKey="Who">WHO</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ksiazek, Tg" uniqKey="Ksiazek T">TG Ksiazek</name></author><author><name sortKey="Erdman, D" uniqKey="Erdman D">D Erdman</name></author><author><name sortKey="Goldsmith, Cs" uniqKey="Goldsmith C">CS Goldsmith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author><author><name sortKey="Gunther, S" uniqKey="Gunther S">S Gunther</name></author><author><name sortKey="Preiser, W" uniqKey="Preiser W">W Preiser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS 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