Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides.
Identifieur interne : 005083 ( Main/Exploration ); précédent : 005082; suivant : 005084Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides.
Auteurs : Berend Jan Bosch [Pays-Bas] ; Byron E E. Martina ; Ruurd Van Der Zee ; Jean Lepault ; Bert Jan Haijema ; Cees Versluis ; Albert J R. Heck ; Raoul De Groot ; Albert D M E. Osterhaus ; Peter J M. RottierSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2004.
Descripteurs français
- KwdFr :
- Alignement de séquences, Animaux, Cellules Vero, Données de séquences moléculaires, Fusion membranaire, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (génétique), Glycoprotéines membranaires (métabolisme), Glycoprotéines membranaires (usage thérapeutique), Peptides (génétique), Peptides (usage thérapeutique), Protéines de l'enveloppe virale (génétique), Protéines de l'enveloppe virale (métabolisme), Protéines de l'enveloppe virale (usage thérapeutique), Souris, Spectrométrie de masse (), Structure quaternaire des protéines, Structure secondaire des protéines, Syndrome respiratoire aigu sévère (traitement médicamenteux), Séquence d'acides aminés, Virus du SRAS (génétique), Virus du SRAS (métabolisme).
- MESH :
- génétique : Glycoprotéines membranaires, Peptides, Protéines de l'enveloppe virale, Virus du SRAS.
- métabolisme : Glycoprotéines membranaires, Protéines de l'enveloppe virale, Virus du SRAS.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- usage thérapeutique : Glycoprotéines membranaires, Peptides, Protéines de l'enveloppe virale.
- Alignement de séquences, Animaux, Cellules Vero, Données de séquences moléculaires, Fusion membranaire, Glycoprotéine de spicule des coronavirus, Souris, Spectrométrie de masse, Structure quaternaire des protéines, Structure secondaire des protéines, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Chlorocebus aethiops, Mass Spectrometry (methods), Membrane Fusion, Membrane Glycoproteins (genetics), Membrane Glycoproteins (metabolism), Membrane Glycoproteins (therapeutic use), Mice, Molecular Sequence Data, Peptides (genetics), Peptides (therapeutic use), Protein Structure, Quaternary, Protein Structure, Secondary, SARS Virus (genetics), SARS Virus (metabolism), Sequence Alignment, Severe Acute Respiratory Syndrome (drug therapy), Spike Glycoprotein, Coronavirus, Vero Cells, Viral Envelope Proteins (genetics), Viral Envelope Proteins (metabolism), Viral Envelope Proteins (therapeutic use).
- MESH :
- chemical , genetics : Membrane Glycoproteins, Peptides, Viral Envelope Proteins.
- chemical , metabolism : Membrane Glycoproteins, Viral Envelope Proteins.
- drug therapy : Severe Acute Respiratory Syndrome.
- genetics : SARS Virus.
- metabolism : SARS Virus.
- methods : Mass Spectrometry.
- chemical , therapeutic use : Membrane Glycoproteins, Peptides, Viral Envelope Proteins.
- Amino Acid Sequence, Animals, Chlorocebus aethiops, Membrane Fusion, Mice, Molecular Sequence Data, Protein Structure, Quaternary, Protein Structure, Secondary, Sequence Alignment, Spike Glycoprotein, Coronavirus, Vero Cells.
Abstract
The coronavirus SARS-CoV is the primary cause of the life-threatening severe acute respiratory syndrome (SARS). With the aim of developing therapeutic agents, we have tested peptides derived from the membrane-proximal (HR2) and membrane-distal (HR1) heptad repeat region of the spike protein as inhibitors of SARS-CoV infection of Vero cells. It appeared that HR2 peptides, but not HR1 peptides, were inhibitory. Their efficacy was, however, significantly lower than that of corresponding HR2 peptides of the murine coronavirus mouse hepatitis virus (MHV) in inhibiting MHV infection. Biochemical and electron microscopical analyses showed that, when mixed, SARS-CoV HR1 and HR2 peptides assemble into a six-helix bundle consisting of HR1 as a central triple-stranded coiled coil in association with three HR2 alpha-helices oriented in an antiparallel manner. The stability of this complex, as measured by its resistance to heat dissociation, appeared to be much lower than that of the corresponding MHV complex, which may explain the different inhibitory potencies of the HR2 peptides. Analogous to other class I viral fusion proteins, the six-helix complex supposedly represents a postfusion conformation that is formed after insertion of the fusion peptide, proposed here for coronaviruses to be located immediately upstream of HR1, into the target membrane. The resulting close apposition of fusion peptide and spike transmembrane domain facilitates membrane fusion. The inhibitory potency of the SARS-CoV HR2-peptides provides an attractive basis for the development of a therapeutic drug for SARS.
DOI: 10.1073/pnas.0400576101
PubMed: 15150417
Affiliations:
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Rottier</name></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Chlorocebus aethiops</term><term>Mass Spectrometry (methods)</term><term>Membrane Fusion</term><term>Membrane Glycoproteins (genetics)</term><term>Membrane Glycoproteins (metabolism)</term><term>Membrane Glycoproteins (therapeutic use)</term><term>Mice</term><term>Molecular Sequence Data</term><term>Peptides (genetics)</term><term>Peptides (therapeutic use)</term><term>Protein Structure, Quaternary</term><term>Protein Structure, Secondary</term><term>SARS Virus (genetics)</term><term>SARS Virus (metabolism)</term><term>Sequence Alignment</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Spike Glycoprotein, Coronavirus</term><term>Vero Cells</term><term>Viral Envelope Proteins (genetics)</term><term>Viral Envelope Proteins (metabolism)</term><term>Viral Envelope Proteins (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences</term><term>Animaux</term><term>Cellules Vero</term><term>Données de séquences moléculaires</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires (génétique)</term><term>Glycoprotéines membranaires (métabolisme)</term><term>Glycoprotéines membranaires (usage thérapeutique)</term><term>Peptides (génétique)</term><term>Peptides (usage thérapeutique)</term><term>Protéines de l'enveloppe virale (génétique)</term><term>Protéines de l'enveloppe virale (métabolisme)</term><term>Protéines de l'enveloppe virale (usage thérapeutique)</term><term>Souris</term><term>Spectrométrie de masse ()</term><term>Structure quaternaire des protéines</term><term>Structure secondaire des protéines</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Séquence d'acides aminés</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Membrane Glycoproteins</term><term>Peptides</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glycoprotéines membranaires</term><term>Peptides</term><term>Protéines de l'enveloppe virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Mass Spectrometry</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéines membranaires</term><term>Protéines de l'enveloppe virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Membrane Glycoproteins</term><term>Peptides</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Glycoprotéines membranaires</term><term>Peptides</term><term>Protéines de l'enveloppe virale</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Chlorocebus aethiops</term><term>Membrane Fusion</term><term>Mice</term><term>Molecular Sequence Data</term><term>Protein Structure, Quaternary</term><term>Protein Structure, Secondary</term><term>Sequence Alignment</term><term>Spike Glycoprotein, Coronavirus</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term><term>Animaux</term><term>Cellules Vero</term><term>Données de séquences moléculaires</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus</term><term>Souris</term><term>Spectrométrie de masse</term><term>Structure quaternaire des protéines</term><term>Structure secondaire des protéines</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The coronavirus SARS-CoV is the primary cause of the life-threatening severe acute respiratory syndrome (SARS). With the aim of developing therapeutic agents, we have tested peptides derived from the membrane-proximal (HR2) and membrane-distal (HR1) heptad repeat region of the spike protein as inhibitors of SARS-CoV infection of Vero cells. It appeared that HR2 peptides, but not HR1 peptides, were inhibitory. Their efficacy was, however, significantly lower than that of corresponding HR2 peptides of the murine coronavirus mouse hepatitis virus (MHV) in inhibiting MHV infection. Biochemical and electron microscopical analyses showed that, when mixed, SARS-CoV HR1 and HR2 peptides assemble into a six-helix bundle consisting of HR1 as a central triple-stranded coiled coil in association with three HR2 alpha-helices oriented in an antiparallel manner. The stability of this complex, as measured by its resistance to heat dissociation, appeared to be much lower than that of the corresponding MHV complex, which may explain the different inhibitory potencies of the HR2 peptides. Analogous to other class I viral fusion proteins, the six-helix complex supposedly represents a postfusion conformation that is formed after insertion of the fusion peptide, proposed here for coronaviruses to be located immediately upstream of HR1, into the target membrane. The resulting close apposition of fusion peptide and spike transmembrane domain facilitates membrane fusion. The inhibitory potency of the SARS-CoV HR2-peptides provides an attractive basis for the development of a therapeutic drug for SARS.</div></front></TEI><affiliations><list><country><li>Pays-Bas</li></country><region><li>Utrecht (province)</li></region><settlement><li>Utrecht</li></settlement><orgName><li>Université d'Utrecht</li></orgName></list><tree><noCountry><name sortKey="De Groot, Raoul" sort="De Groot, Raoul" uniqKey="De Groot R" first="Raoul" last="De Groot">Raoul De Groot</name><name sortKey="Haijema, Bert Jan" sort="Haijema, Bert Jan" uniqKey="Haijema B" first="Bert Jan" last="Haijema">Bert Jan Haijema</name><name sortKey="Heck, Albert J R" sort="Heck, Albert J R" uniqKey="Heck A" first="Albert J R" last="Heck">Albert J R. Heck</name><name sortKey="Lepault, Jean" sort="Lepault, Jean" uniqKey="Lepault J" first="Jean" last="Lepault">Jean Lepault</name><name sortKey="Martina, Byron E E" sort="Martina, Byron E E" uniqKey="Martina B" first="Byron E E" last="Martina">Byron E E. Martina</name><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D M E" last="Osterhaus">Albert D M E. Osterhaus</name><name sortKey="Rottier, Peter J M" sort="Rottier, Peter J M" uniqKey="Rottier P" first="Peter J M" last="Rottier">Peter J M. Rottier</name><name sortKey="Van Der Zee, Ruurd" sort="Van Der Zee, Ruurd" uniqKey="Van Der Zee R" first="Ruurd" last="Van Der Zee">Ruurd Van Der Zee</name><name sortKey="Versluis, Cees" sort="Versluis, Cees" uniqKey="Versluis C" first="Cees" last="Versluis">Cees Versluis</name></noCountry><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="Bosch, Berend Jan" sort="Bosch, Berend Jan" uniqKey="Bosch B" first="Berend Jan" last="Bosch">Berend Jan Bosch</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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