Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase : SARS-CoV: A scénario of modern drug design
Identifieur interne : 004640 ( Main/Merge ); précédent : 004639; suivant : 004641Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase : SARS-CoV: A scénario of modern drug design
Auteurs : LUHUA LAI [République populaire de Chine] ; XIAOFENG HAN [République populaire de Chine] ; HAO CHEN [République populaire de Chine] ; PING WEI [République populaire de Chine] ; CHANGKANG HUANG [République populaire de Chine] ; SHIYONG LIU [République populaire de Chine] ; KEQIANG FAN [République populaire de Chine] ; LU ZHOU [République populaire de Chine] ; ZHENMING LIU [République populaire de Chine] ; JIANFENG PEI [République populaire de Chine] ; YING LIU [République populaire de Chine]Source :
- Current pharmaceutical design [ 1381-6128 ] ; 2006.
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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.
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CHEN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Theoretical Biology, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement 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type="capitale">Pékin</region></placeName></affiliation></author><author><name sortKey="Changkang Huang" sort="Changkang Huang" uniqKey="Changkang Huang" last="Changkang Huang">CHANGKANG HUANG</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Shiyong Liu" sort="Shiyong Liu" uniqKey="Shiyong Liu" last="Shiyong 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Chine</country><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="Keqiang Fan" sort="Keqiang Fan" uniqKey="Keqiang Fan" last="Keqiang Fan">KEQIANG FAN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Lu Zhou" sort="Lu Zhou" uniqKey="Lu Zhou" last="Lu Zhou">LU ZHOU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Zhenming Liu" sort="Zhenming Liu" uniqKey="Zhenming Liu" last="Zhenming Liu">ZHENMING LIU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Jianfeng Pei" sort="Jianfeng Pei" uniqKey="Jianfeng Pei" last="Jianfeng Pei">JIANFENG PEI</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Ying Liu" sort="Ying Liu" uniqKey="Ying Liu" last="Ying Liu">YING LIU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 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type="wicri:Area/Main/Merge">004640</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase : SARS-CoV: A scénario of modern drug design</title><author><name sortKey="Luhua Lai" sort="Luhua Lai" uniqKey="Luhua Lai" last="Luhua Lai">LUHUA LAI</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Theoretical Biology, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Xiaofeng Han" sort="Xiaofeng Han" uniqKey="Xiaofeng Han" last="Xiaofeng Han">XIAOFENG HAN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Theoretical Biology, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Hao Chen" sort="Hao Chen" uniqKey="Hao Chen" last="Hao Chen">HAO CHEN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Theoretical Biology, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Ping Wei" sort="Ping Wei" uniqKey="Ping Wei" last="Ping Wei">PING WEI</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Changkang Huang" sort="Changkang Huang" uniqKey="Changkang Huang" last="Changkang Huang">CHANGKANG HUANG</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Shiyong Liu" sort="Shiyong Liu" uniqKey="Shiyong Liu" last="Shiyong Liu">SHIYONG LIU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Theoretical Biology, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Keqiang Fan" sort="Keqiang Fan" uniqKey="Keqiang Fan" last="Keqiang Fan">KEQIANG FAN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Lu Zhou" sort="Lu Zhou" uniqKey="Lu Zhou" last="Lu Zhou">LU ZHOU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Zhenming Liu" sort="Zhenming Liu" uniqKey="Zhenming Liu" last="Zhenming Liu">ZHENMING LIU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Jianfeng Pei" sort="Jianfeng Pei" uniqKey="Jianfeng Pei" last="Jianfeng Pei">JIANFENG PEI</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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="Ying Liu" sort="Ying Liu" uniqKey="Ying Liu" last="Ying Liu">YING LIU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University</s1><s2>Beijing 100871</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>République populaire de Chine</country><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></analytic><series><title level="j" type="main">Current pharmaceutical design</title><title level="j" type="abbreviated">Curr. pharm. des.</title><idno type="ISSN">1381-6128</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Current pharmaceutical design</title><title level="j" type="abbreviated">Curr. pharm. des.</title><idno type="ISSN">1381-6128</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Coronavirus</term><term>Design</term><term>Enzyme inhibitor</term><term>Mechanism of action</term><term>Molecular structure</term><term>Peptidases</term><term>Quaternary structure</term><term>Research and development</term><term>Review</term><term>Selectivity</term><term>Severe acute respiratory syndrome</term><term>Structure activity relation</term><term>Substrate</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Inhibiteur enzyme</term><term>Substrat</term><term>Sélectivité</term><term>Coronavirus</term><term>Relation structure activité</term><term>Syndrome respiratoire aigu sévère</term><term>Peptidases</term><term>Mécanisme action</term><term>Article synthèse</term><term>Structure moléculaire</term><term>Recherche développement</term><term>Antiviral</term><term>Conception</term><term>Structure quaternaire</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 IC<sub>50</sub> 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><country name="République populaire de Chine"><noRegion><name sortKey="Luhua Lai" sort="Luhua Lai" uniqKey="Luhua Lai" last="Luhua Lai">LUHUA LAI</name></noRegion><name sortKey="Changkang Huang" sort="Changkang Huang" uniqKey="Changkang Huang" last="Changkang Huang">CHANGKANG HUANG</name><name sortKey="Hao Chen" sort="Hao Chen" uniqKey="Hao Chen" last="Hao Chen">HAO CHEN</name><name sortKey="Hao Chen" sort="Hao Chen" uniqKey="Hao Chen" last="Hao Chen">HAO CHEN</name><name sortKey="Jianfeng Pei" sort="Jianfeng Pei" uniqKey="Jianfeng Pei" last="Jianfeng Pei">JIANFENG PEI</name><name sortKey="Keqiang Fan" sort="Keqiang Fan" uniqKey="Keqiang Fan" last="Keqiang Fan">KEQIANG FAN</name><name sortKey="Lu Zhou" sort="Lu Zhou" uniqKey="Lu Zhou" last="Lu Zhou">LU ZHOU</name><name sortKey="Luhua Lai" sort="Luhua Lai" uniqKey="Luhua Lai" last="Luhua Lai">LUHUA LAI</name><name sortKey="Ping Wei" sort="Ping Wei" uniqKey="Ping Wei" last="Ping Wei">PING WEI</name><name sortKey="Shiyong Liu" sort="Shiyong Liu" uniqKey="Shiyong Liu" last="Shiyong Liu">SHIYONG LIU</name><name sortKey="Shiyong Liu" sort="Shiyong Liu" uniqKey="Shiyong Liu" last="Shiyong Liu">SHIYONG LIU</name><name sortKey="Xiaofeng Han" sort="Xiaofeng Han" uniqKey="Xiaofeng Han" last="Xiaofeng Han">XIAOFENG HAN</name><name sortKey="Xiaofeng Han" sort="Xiaofeng Han" uniqKey="Xiaofeng Han" last="Xiaofeng Han">XIAOFENG HAN</name><name sortKey="Ying Liu" sort="Ying Liu" uniqKey="Ying Liu" last="Ying Liu">YING LIU</name><name sortKey="Zhenming Liu" sort="Zhenming Liu" uniqKey="Zhenming Liu" last="Zhenming Liu">ZHENMING LIU</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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