Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.
Identifieur interne : 003D57 ( Main/Exploration ); précédent : 003D56; suivant : 003D58Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.
Auteurs : Luhua Lai [République populaire de Chine] ; Xiaofeng Han ; Hao Chen ; Ping Wei ; Changkang Huang ; Shiyong Liu ; Keqiang Fan ; Lu Zhou ; Zhenming Liu ; Jianfeng Pei ; Ying LiuSource :
- Current pharmaceutical design [ 1873-4286 ] ; 2006.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (), Antiviraux (pharmacologie), Conception assistée par ordinateur, Conception de médicament, Cysteine endopeptidases (), Domaine catalytique, Humains, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Modèles chimiques, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation dose-effet des médicaments, Relation structure-activité, Spécificité du substrat, Structure quaternaire des protéines, Virus du SRAS (), Virus du SRAS (enzymologie), Évaluation préclinique de médicament ().
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Antiviraux, Inhibiteurs de protéases.
- Animaux, Antiviraux, Conception assistée par ordinateur, Conception de médicament, Cysteine endopeptidases, Domaine catalytique, Humains, Inhibiteurs de protéases, Modèles chimiques, Protéines virales, Relation dose-effet des médicaments, Relation structure-activité, Spécificité du substrat, Structure quaternaire des protéines, Virus du SRAS, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Catalytic Domain, Computer-Aided Design, Cysteine Endopeptidases (chemistry), Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical (methods), Humans, Models, Chemical, Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Protein Structure, Quaternary, SARS Virus (drug effects), SARS Virus (enzymology), Structure-Activity Relationship, Substrate Specificity, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Protease Inhibitors, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Protease Inhibitors.
- drug effects : SARS Virus.
- enzymology : SARS Virus.
- methods : Drug Evaluation, Preclinical.
- Animals, Catalytic Domain, Computer-Aided Design, Dose-Response Relationship, Drug, Drug Design, Humans, Models, Chemical, Protein Structure, Quaternary, Structure-Activity Relationship, Substrate Specificity.
Abstract
The SARS coronavirus 3C-like proteinase is recognized as a potential drug design target for the treatment of severe acute respiratory syndrome. In the past few years, much work has been done to understand the catalytic mechanism of this target protein and to design its selective inhibitors. The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction. Quantitative dissociation constants have been reported for the dimer by using analytic ultracentrifuge, gel filtration and enzyme assays. Though the enzyme is a cysteine protease with a chymotrypsin fold, SARS 3C-like proteinase follows the general base catalytic mechanism similar to chymotrypsin. As the enzyme can cut eleven different sites on the viral polyprotein, the substrate specificity has been studied by synthesized peptides corresponding or similar to the cleavage sites on the polyprotein. Predictive model was built for substrate structure and activity relationships and can be applied in inhibitor design. Due to the lack of potential drugs for the treatment of SARS, the discovery of inhibitors against SARS 3C-like proteinase, which can potentially be optimized as drugs appears to be highly desirable. Various groups have been working on inhibitor discovery by virtual screening, compound library screening, modification of existing compounds or natural products. High-throughput in vitro assays, auto-cleavage assays and viral replication assays have been developed for inhibition activity tests. Inhibitors with IC50 values as low as 60 nM have been reported.
DOI: 10.2174/138161206779010396
PubMed: 17168761
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 001F55
- to stream PubMed, to step Curation: 001F55
- to stream PubMed, to step Checkpoint: 002045
- to stream Ncbi, to step Merge: 001803
- to stream Ncbi, to step Curation: 001803
- to stream Ncbi, to step Checkpoint: 001803
- to stream Main, to step Merge: 003F30
- to stream Main, to step Curation: 003D57
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.</title><author><name sortKey="Lai, Luhua" sort="Lai, Luhua" uniqKey="Lai L" first="Luhua" last="Lai">Luhua Lai</name><affiliation wicri:level="4"><nlm:affiliation>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. lhlai@pku.edu.cn</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName><orgName type="university">Université de Pékin</orgName><placeName><settlement type="city">Pékin</settlement><region type="capitale">Pékin</region></placeName></affiliation></author><author><name sortKey="Han, Xiaofeng" sort="Han, Xiaofeng" uniqKey="Han X" first="Xiaofeng" last="Han">Xiaofeng Han</name></author><author><name sortKey="Chen, Hao" sort="Chen, Hao" uniqKey="Chen H" first="Hao" last="Chen">Hao Chen</name></author><author><name sortKey="Wei, Ping" sort="Wei, Ping" uniqKey="Wei P" first="Ping" last="Wei">Ping Wei</name></author><author><name sortKey="Huang, Changkang" sort="Huang, Changkang" uniqKey="Huang C" first="Changkang" last="Huang">Changkang Huang</name></author><author><name sortKey="Liu, Shiyong" sort="Liu, Shiyong" uniqKey="Liu S" first="Shiyong" last="Liu">Shiyong Liu</name></author><author><name sortKey="Fan, Keqiang" sort="Fan, Keqiang" uniqKey="Fan K" first="Keqiang" last="Fan">Keqiang Fan</name></author><author><name sortKey="Zhou, Lu" sort="Zhou, Lu" uniqKey="Zhou L" first="Lu" last="Zhou">Lu Zhou</name></author><author><name sortKey="Liu, Zhenming" sort="Liu, Zhenming" uniqKey="Liu Z" first="Zhenming" last="Liu">Zhenming Liu</name></author><author><name sortKey="Pei, Jianfeng" sort="Pei, Jianfeng" uniqKey="Pei J" first="Jianfeng" last="Pei">Jianfeng Pei</name></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2006">2006</date><idno type="RBID">pubmed:17168761</idno><idno type="pmid">17168761</idno><idno type="doi">10.2174/138161206779010396</idno><idno type="wicri:Area/PubMed/Corpus">001F55</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001F55</idno><idno type="wicri:Area/PubMed/Curation">001F55</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001F55</idno><idno type="wicri:Area/PubMed/Checkpoint">002045</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002045</idno><idno type="wicri:Area/Ncbi/Merge">001803</idno><idno type="wicri:Area/Ncbi/Curation">001803</idno><idno type="wicri:Area/Ncbi/Checkpoint">001803</idno><idno type="wicri:Area/Main/Merge">003F30</idno><idno type="wicri:Area/Main/Curation">003D57</idno><idno type="wicri:Area/Main/Exploration">003D57</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.</title><author><name sortKey="Lai, Luhua" sort="Lai, Luhua" uniqKey="Lai L" first="Luhua" last="Lai">Luhua Lai</name><affiliation wicri:level="4"><nlm:affiliation>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. lhlai@pku.edu.cn</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName><orgName type="university">Université de Pékin</orgName><placeName><settlement type="city">Pékin</settlement><region type="capitale">Pékin</region></placeName></affiliation></author><author><name sortKey="Han, Xiaofeng" sort="Han, Xiaofeng" uniqKey="Han X" first="Xiaofeng" last="Han">Xiaofeng Han</name></author><author><name sortKey="Chen, Hao" sort="Chen, Hao" uniqKey="Chen H" first="Hao" last="Chen">Hao Chen</name></author><author><name sortKey="Wei, Ping" sort="Wei, Ping" uniqKey="Wei P" first="Ping" last="Wei">Ping Wei</name></author><author><name sortKey="Huang, Changkang" sort="Huang, Changkang" uniqKey="Huang C" first="Changkang" last="Huang">Changkang Huang</name></author><author><name sortKey="Liu, Shiyong" sort="Liu, Shiyong" uniqKey="Liu S" first="Shiyong" last="Liu">Shiyong Liu</name></author><author><name sortKey="Fan, Keqiang" sort="Fan, Keqiang" uniqKey="Fan K" first="Keqiang" last="Fan">Keqiang Fan</name></author><author><name sortKey="Zhou, Lu" sort="Zhou, Lu" uniqKey="Zhou L" first="Lu" last="Zhou">Lu Zhou</name></author><author><name sortKey="Liu, Zhenming" sort="Liu, Zhenming" uniqKey="Liu Z" first="Zhenming" last="Liu">Zhenming Liu</name></author><author><name sortKey="Pei, Jianfeng" sort="Pei, Jianfeng" uniqKey="Pei J" first="Jianfeng" last="Pei">Jianfeng Pei</name></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name></author></analytic><series><title level="j">Current pharmaceutical design</title><idno type="eISSN">1873-4286</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Catalytic Domain</term><term>Computer-Aided Design</term><term>Cysteine Endopeptidases (chemistry)</term><term>Dose-Response Relationship, Drug</term><term>Drug Design</term><term>Drug Evaluation, Preclinical (methods)</term><term>Humans</term><term>Models, Chemical</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (pharmacology)</term><term>Protein Structure, Quaternary</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>Structure-Activity Relationship</term><term>Substrate Specificity</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Conception assistée par ordinateur</term><term>Conception de médicament</term><term>Cysteine endopeptidases ()</term><term>Domaine catalytique</term><term>Humains</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Modèles chimiques</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Spécificité du substrat</term><term>Structure quaternaire des protéines</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term><term>Évaluation préclinique de médicament ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Evaluation, Preclinical</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Catalytic Domain</term><term>Computer-Aided Design</term><term>Dose-Response Relationship, Drug</term><term>Drug Design</term><term>Humans</term><term>Models, Chemical</term><term>Protein Structure, Quaternary</term><term>Structure-Activity Relationship</term><term>Substrate Specificity</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antiviraux</term><term>Conception assistée par ordinateur</term><term>Conception de médicament</term><term>Cysteine endopeptidases</term><term>Domaine catalytique</term><term>Humains</term><term>Inhibiteurs de protéases</term><term>Modèles chimiques</term><term>Protéines virales</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Spécificité du substrat</term><term>Structure quaternaire des protéines</term><term>Virus du SRAS</term><term>Évaluation préclinique de médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The SARS coronavirus 3C-like proteinase is recognized as a potential drug design target for the treatment of severe acute respiratory syndrome. In the past few years, much work has been done to understand the catalytic mechanism of this target protein and to design its selective inhibitors. The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction. Quantitative dissociation constants have been reported for the dimer by using analytic ultracentrifuge, gel filtration and enzyme assays. Though the enzyme is a cysteine protease with a chymotrypsin fold, SARS 3C-like proteinase follows the general base catalytic mechanism similar to chymotrypsin. As the enzyme can cut eleven different sites on the viral polyprotein, the substrate specificity has been studied by synthesized peptides corresponding or similar to the cleavage sites on the polyprotein. Predictive model was built for substrate structure and activity relationships and can be applied in inhibitor design. Due to the lack of potential drugs for the treatment of SARS, the discovery of inhibitors against SARS 3C-like proteinase, which can potentially be optimized as drugs appears to be highly desirable. Various groups have been working on inhibitor discovery by virtual screening, compound library screening, modification of existing compounds or natural products. High-throughput in vitro assays, auto-cleavage assays and viral replication assays have been developed for inhibition activity tests. Inhibitors with IC50 values as low as 60 nM have been reported.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Pékin</li></region><settlement><li>Pékin</li></settlement><orgName><li>Université de Pékin</li></orgName></list><tree><noCountry><name sortKey="Chen, Hao" sort="Chen, Hao" uniqKey="Chen H" first="Hao" last="Chen">Hao Chen</name><name sortKey="Fan, Keqiang" sort="Fan, Keqiang" uniqKey="Fan K" first="Keqiang" last="Fan">Keqiang Fan</name><name sortKey="Han, Xiaofeng" sort="Han, Xiaofeng" uniqKey="Han X" first="Xiaofeng" last="Han">Xiaofeng Han</name><name sortKey="Huang, Changkang" sort="Huang, Changkang" uniqKey="Huang C" first="Changkang" last="Huang">Changkang Huang</name><name sortKey="Liu, Shiyong" sort="Liu, Shiyong" uniqKey="Liu S" first="Shiyong" last="Liu">Shiyong Liu</name><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><name sortKey="Liu, Zhenming" sort="Liu, Zhenming" uniqKey="Liu Z" first="Zhenming" last="Liu">Zhenming Liu</name><name sortKey="Pei, Jianfeng" sort="Pei, Jianfeng" uniqKey="Pei J" first="Jianfeng" last="Pei">Jianfeng Pei</name><name sortKey="Wei, Ping" sort="Wei, Ping" uniqKey="Wei P" first="Ping" last="Wei">Ping Wei</name><name sortKey="Zhou, Lu" sort="Zhou, Lu" uniqKey="Zhou L" first="Lu" last="Zhou">Lu Zhou</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Lai, Luhua" sort="Lai, Luhua" uniqKey="Lai L" first="Luhua" last="Lai">Luhua Lai</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 003D57 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 003D57 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:17168761
|texte= Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:17168761" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |