Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry.
Identifieur interne : 004781 ( Main/Exploration ); précédent : 004780; suivant : 004782Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry.
Auteurs : Graham Simmons [États-Unis] ; Dhaval N. Gosalia ; Andrew J. Rennekamp ; Jacqueline D. Reeves ; Scott L. Diamond ; Paul BatesSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2005.
Descripteurs français
- KwdFr :
- Cathepsine L, Cathepsines (antagonistes et inhibiteurs), Cathepsines (métabolisme), Cysteine endopeptidases (métabolisme), Fusion membranaire (), Fusion membranaire (physiologie), Humains, Inhibiteurs de protéases (pharmacologie), Lignée cellulaire, Membrane cellulaire (), Membrane cellulaire (métabolisme), Structure moléculaire, Syndrome respiratoire aigu sévère (), Syndrome respiratoire aigu sévère (enzymologie), Syndrome respiratoire aigu sévère (virologie), Température, Virus du SRAS (), Virus du SRAS (physiologie).
- MESH :
- antagonistes et inhibiteurs : Cathepsines.
- enzymologie : Syndrome respiratoire aigu sévère.
- métabolisme : Cathepsines, Cysteine endopeptidases, Membrane cellulaire.
- pharmacologie : Inhibiteurs de protéases.
- physiologie : Fusion membranaire, Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Cathepsine L, Fusion membranaire, Humains, Lignée cellulaire, Membrane cellulaire, Structure moléculaire, Syndrome respiratoire aigu sévère, Température, Virus du SRAS.
English descriptors
- KwdEn :
- Cathepsin L, Cathepsins (antagonists & inhibitors), Cathepsins (metabolism), Cell Line, Cell Membrane (chemistry), Cell Membrane (drug effects), Cell Membrane (metabolism), Cysteine Endopeptidases (metabolism), Humans, Membrane Fusion (drug effects), Membrane Fusion (physiology), Molecular Structure, Protease Inhibitors (pharmacology), SARS Virus (drug effects), SARS Virus (physiology), Severe Acute Respiratory Syndrome (enzymology), Severe Acute Respiratory Syndrome (prevention & control), Severe Acute Respiratory Syndrome (virology), Temperature.
- MESH :
- chemical , antagonists & inhibitors : Cathepsins.
- chemical , metabolism : Cathepsins, Cysteine Endopeptidases.
- chemical , pharmacology : Protease Inhibitors.
- chemical : Cathepsin L.
- chemistry : Cell Membrane.
- drug effects : Cell Membrane, Membrane Fusion, SARS Virus.
- enzymology : Severe Acute Respiratory Syndrome.
- metabolism : Cell Membrane.
- physiology : Membrane Fusion, SARS Virus.
- prevention & control : Severe Acute Respiratory Syndrome.
- virology : Severe Acute Respiratory Syndrome.
- Cell Line, Humans, Molecular Structure, Temperature.
Abstract
Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-associated virus. In addition, SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.
DOI: 10.1073/pnas.0505577102
PubMed: 16081529
Affiliations:
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Le document en format XML
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Gosalia</name></author><author><name sortKey="Rennekamp, Andrew J" sort="Rennekamp, Andrew J" uniqKey="Rennekamp A" first="Andrew J" last="Rennekamp">Andrew J. Rennekamp</name></author><author><name sortKey="Reeves, Jacqueline D" sort="Reeves, Jacqueline D" uniqKey="Reeves J" first="Jacqueline D" last="Reeves">Jacqueline D. Reeves</name></author><author><name sortKey="Diamond, Scott L" sort="Diamond, Scott L" uniqKey="Diamond S" first="Scott L" last="Diamond">Scott L. 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Gosalia</name></author><author><name sortKey="Rennekamp, Andrew J" sort="Rennekamp, Andrew J" uniqKey="Rennekamp A" first="Andrew J" last="Rennekamp">Andrew J. Rennekamp</name></author><author><name sortKey="Reeves, Jacqueline D" sort="Reeves, Jacqueline D" uniqKey="Reeves J" first="Jacqueline D" last="Reeves">Jacqueline D. Reeves</name></author><author><name sortKey="Diamond, Scott L" sort="Diamond, Scott L" uniqKey="Diamond S" first="Scott L" last="Diamond">Scott L. Diamond</name></author><author><name sortKey="Bates, Paul" sort="Bates, Paul" uniqKey="Bates P" first="Paul" last="Bates">Paul Bates</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="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cathepsin L</term><term>Cathepsins (antagonists & inhibitors)</term><term>Cathepsins (metabolism)</term><term>Cell Line</term><term>Cell Membrane (chemistry)</term><term>Cell Membrane (drug effects)</term><term>Cell Membrane (metabolism)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Humans</term><term>Membrane Fusion (drug effects)</term><term>Membrane Fusion (physiology)</term><term>Molecular Structure</term><term>Protease Inhibitors (pharmacology)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (enzymology)</term><term>Severe Acute Respiratory Syndrome (prevention & control)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Temperature</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cathepsine L</term><term>Cathepsines (antagonistes et inhibiteurs)</term><term>Cathepsines (métabolisme)</term><term>Cysteine endopeptidases (métabolisme)</term><term>Fusion membranaire ()</term><term>Fusion membranaire (physiologie)</term><term>Humains</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Lignée cellulaire</term><term>Membrane cellulaire ()</term><term>Membrane cellulaire (métabolisme)</term><term>Structure moléculaire</term><term>Syndrome respiratoire aigu sévère ()</term><term>Syndrome respiratoire aigu sévère (enzymologie)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Température</term><term>Virus du SRAS ()</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Cathepsins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cathepsins</term><term>Cysteine Endopeptidases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Cathepsin L</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Cathepsines</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Membrane</term><term>Membrane Fusion</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cathepsines</term><term>Cysteine endopeptidases</term><term>Membrane cellulaire</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Fusion membranaire</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Membrane Fusion</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Humans</term><term>Molecular Structure</term><term>Temperature</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cathepsine L</term><term>Fusion membranaire</term><term>Humains</term><term>Lignée cellulaire</term><term>Membrane cellulaire</term><term>Structure moléculaire</term><term>Syndrome respiratoire aigu sévère</term><term>Température</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-associated virus. In addition, SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><noCountry><name sortKey="Bates, Paul" sort="Bates, Paul" uniqKey="Bates P" first="Paul" last="Bates">Paul Bates</name><name sortKey="Diamond, Scott L" sort="Diamond, Scott L" uniqKey="Diamond S" first="Scott L" last="Diamond">Scott L. Diamond</name><name sortKey="Gosalia, Dhaval N" sort="Gosalia, Dhaval N" uniqKey="Gosalia D" first="Dhaval N" last="Gosalia">Dhaval N. Gosalia</name><name sortKey="Reeves, Jacqueline D" sort="Reeves, Jacqueline D" uniqKey="Reeves J" first="Jacqueline D" last="Reeves">Jacqueline D. Reeves</name><name sortKey="Rennekamp, Andrew J" sort="Rennekamp, Andrew J" uniqKey="Rennekamp A" first="Andrew J" last="Rennekamp">Andrew J. Rennekamp</name></noCountry><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Simmons, Graham" sort="Simmons, Graham" uniqKey="Simmons G" first="Graham" last="Simmons">Graham Simmons</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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