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 : 005B12 ( Main/Exploration ); précédent : 005B11; suivant : 005B13Interaction 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 : (British edition) [ 0140-6736 ] ; 2004.
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Abstract
Background 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). Methods 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. Findings 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 α-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. Interpretation 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.
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Debnath</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Po Tien" sort="Po Tien" uniqKey="Po Tien" last="Po Tien">PO TIEN</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Modern Virology Research Center, Wuhan University</s1><s2>Wuhan</s2><s3>CHN</s3><sZ>2 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName><orgName type="university">Université de Wuhan</orgName></affiliation></author><author><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">04-0205676</idno><date when="2004">2004</date><idno type="stanalyst">PASCAL 04-0205676 INIST</idno><idno type="RBID">Pascal:04-0205676</idno><idno type="wicri:Area/PascalFrancis/Corpus">000915</idno><idno type="wicri:Area/PascalFrancis/Curation">000075</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000822</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000822</idno><idno type="wicri:doubleKey">0140-6736:2004:Shuwen Liu:interaction:between:heptad</idno><idno type="wicri:Area/Main/Merge">005F73</idno><idno type="wicri:Area/Main/Curation">005B12</idno><idno type="wicri:Area/Main/Exploration">005B12</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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</title><author><name sortKey="Shuwen Liu" sort="Shuwen Liu" uniqKey="Shuwen Liu" last="Shuwen Liu">SHUWEN LIU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Gengfu Xiao" sort="Gengfu Xiao" uniqKey="Gengfu Xiao" last="Gengfu Xiao">GENGFU XIAO</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Modern Virology Research Center, Wuhan University</s1><s2>Wuhan</s2><s3>CHN</s3><sZ>2 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName><orgName type="university">Université de Wuhan</orgName></affiliation></author><author><name sortKey="Yibang Chen" sort="Yibang Chen" uniqKey="Yibang Chen" last="Yibang Chen">YIBANG CHEN</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Mount Sinai School of Medicine</s1><s2>New York, NY</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Yuxian He" sort="Yuxian He" uniqKey="Yuxian He" last="Yuxian He">YUXIAN HE</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Jinkui Niu" sort="Jinkui Niu" uniqKey="Jinkui Niu" last="Jinkui Niu">JINKUI NIU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><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"><inist:fA14 i1="03"><s1>Mount Sinai School of Medicine</s1><s2>New York, NY</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Huabao Xiong" sort="Huabao Xiong" uniqKey="Huabao Xiong" last="Huabao Xiong">HUABAO XIONG</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Mount Sinai School of Medicine</s1><s2>New York, NY</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><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"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><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"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Po Tien" sort="Po Tien" uniqKey="Po Tien" last="Po Tien">PO TIEN</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Modern Virology Research Center, Wuhan University</s1><s2>Wuhan</s2><s3>CHN</s3><sZ>2 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName><orgName type="university">Université de Wuhan</orgName></affiliation></author><author><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Lindsley F Kimball Research Institute, New York Blood Center</s1><s2>New York, NY</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Lancet : (British edition)</title><title level="j" type="abbreviated">Lancet : (Br. ed.)</title><idno type="ISSN">0140-6736</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Lancet : (British edition)</title><title level="j" type="abbreviated">Lancet : (Br. ed.)</title><idno type="ISSN">0140-6736</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Associated virus</term><term>Coronavirus</term><term>Human</term><term>Identification</term><term>Inhibitor</term><term>Interaction</term><term>Mechanism of action</term><term>Protein</term><term>Region</term><term>Severe acute respiratory syndrome</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Interaction</term><term>Région</term><term>Protéine</term><term>Virus associé</term><term>Coronavirus</term><term>Mécanisme action</term><term>Identification</term><term>Inhibiteur</term><term>Homme</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Région</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background 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). Methods 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. Findings 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 α-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. Interpretation 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.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Hubei</li><li>État de New York</li></region><settlement><li>Wuhan</li></settlement><orgName><li>Université de Wuhan</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Shuwen Liu" sort="Shuwen Liu" uniqKey="Shuwen Liu" last="Shuwen Liu">SHUWEN LIU</name></region><name sortKey="Debnath, Asim K" sort="Debnath, Asim K" uniqKey="Debnath A" first="Asim K." last="Debnath">Asim K. Debnath</name><name sortKey="Escalante, Carlos R" sort="Escalante, Carlos R" uniqKey="Escalante C" first="Carlos R." last="Escalante">Carlos R. Escalante</name><name sortKey="Farmar, James" sort="Farmar, James" uniqKey="Farmar J" first="James" last="Farmar">James Farmar</name><name sortKey="Huabao Xiong" sort="Huabao Xiong" uniqKey="Huabao Xiong" last="Huabao Xiong">HUABAO XIONG</name><name sortKey="Jinkui Niu" sort="Jinkui Niu" uniqKey="Jinkui Niu" last="Jinkui Niu">JINKUI NIU</name><name sortKey="Shibo Jiang" sort="Shibo Jiang" uniqKey="Shibo Jiang" last="Shibo Jiang">SHIBO JIANG</name><name sortKey="Yibang Chen" sort="Yibang Chen" uniqKey="Yibang Chen" last="Yibang Chen">YIBANG CHEN</name><name sortKey="Yuxian He" sort="Yuxian He" uniqKey="Yuxian He" last="Yuxian He">YUXIAN HE</name></country><country name="République populaire de Chine"><region name="Hubei"><name sortKey="Gengfu Xiao" sort="Gengfu Xiao" uniqKey="Gengfu Xiao" last="Gengfu Xiao">GENGFU XIAO</name></region><name sortKey="Po Tien" sort="Po Tien" uniqKey="Po Tien" last="Po Tien">PO TIEN</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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