Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters
Identifieur interne : 004E04 ( Main/Exploration ); précédent : 004E03; suivant : 004E05Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters
Auteurs : Jiun-Jie Shie [Taïwan] ; Jim-Min Fang [Taïwan] ; Tun-Hsun Kuo [Taïwan] ; Chih-Jung Kuo [Taïwan] ; Po-Huang Liang [Taïwan] ; Hung-Jyun Huang [Taïwan] ; Yin-Ta Wu [Taïwan] ; Jia-Tsrong Jan [Taïwan] ; Yih-Shyun E. Cheng [Taïwan] ; Chi-Huey Wong [Taïwan]Source :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2005.
Descripteurs français
- Pascal (Inist)
- Synthèse chimique, Syndrome respiratoire aigu sévère, Peptidases, Composé peptidomimétique, Ester, Virus syndrome respiratoire aigu sévère, Activité biologique, Inhibiteur protease, Complexe enzyme inhibiteur, Cinnamique acide dérivé, Antiviral, Modèle moléculaire, Composé vinylique, Inhibiteur enzyme, Modélisation, Phénylalaninamide(N-[1-benzyl-3-éthoxycarbonylallyl]-Nα-[4-(diméthylamino)cinnamoyl]), Phénylalanine dérivé.
English descriptors
- KwdEn :
- Antiviral, Biological activity, Chemical synthesis, Cinnamic acid derivatives, Enzyme inhibitor, Ester, Inhibitor enzyme complex, Modeling, Molecular model, Peptidases, Peptidomimetic compound, Protease inhibitor, Severe acute respiratory syndrome, Severe acute respiratory syndrome virus, Vinylic compound.
Abstract
The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide α,β-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 μM), the ketomethylene isosteres and tripeptide α,β-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 = 11-39 μM). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 μM is obtained by condensation of the Phe-Phe dipeptide α,β-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC50 value of 0.18 μM.
Affiliations:
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Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Jan, Jia Tsrong" sort="Jan, Jia Tsrong" uniqKey="Jan J" first="Jia-Tsrong" last="Jan">Jia-Tsrong Jan</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institute of Preventive Medicine, National Defense University</s1><s2>Taipei</s2><s3>TWN</s3><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei</wicri:noRegion></affiliation></author><author><name sortKey="Cheng, Yih Shyun E" sort="Cheng, Yih Shyun E" uniqKey="Cheng Y" first="Yih-Shyun E." last="Cheng">Yih-Shyun E. Cheng</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">05-0491084</idno><date when="2005">2005</date><idno type="stanalyst">PASCAL 05-0491084 INIST</idno><idno type="RBID">Pascal:05-0491084</idno><idno type="wicri:Area/PascalFrancis/Corpus">000577</idno><idno type="wicri:Area/PascalFrancis/Curation">000413</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000623</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000623</idno><idno type="wicri:doubleKey">0968-0896:2005:Shie J:inhibition:of:the</idno><idno type="wicri:Area/Main/Merge">005143</idno><idno type="wicri:Area/Main/Curation">004E04</idno><idno type="wicri:Area/Main/Exploration">004E04</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters</title><author><name sortKey="Shie, Jiun Jie" sort="Shie, Jiun Jie" uniqKey="Shie J" first="Jiun-Jie" last="Shie">Jiun-Jie Shie</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Chemistry, National Taiwan University</s1><s2>Taipei 106</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 106</wicri:noRegion></affiliation></author><author><name sortKey="Fang, Jim Min" sort="Fang, Jim Min" uniqKey="Fang J" first="Jim-Min" last="Fang">Jim-Min Fang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Chemistry, National Taiwan University</s1><s2>Taipei 106</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 106</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Kuo, Tun Hsun" sort="Kuo, Tun Hsun" uniqKey="Kuo T" first="Tun-Hsun" last="Kuo">Tun-Hsun Kuo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biological Chemistry, Academia Sinica</s1><s2>Tuipei 115</s2><s3>TWN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Tuipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Kuo, Chih Jung" sort="Kuo, Chih Jung" uniqKey="Kuo C" first="Chih-Jung" last="Kuo">Chih-Jung Kuo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biological Chemistry, Academia Sinica</s1><s2>Tuipei 115</s2><s3>TWN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Tuipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biological Chemistry, Academia Sinica</s1><s2>Tuipei 115</s2><s3>TWN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Tuipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Hung Jyun" sort="Huang, Hung Jyun" uniqKey="Huang H" first="Hung-Jyun" last="Huang">Hung-Jyun Huang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Chemistry, National Taiwan University</s1><s2>Taipei 106</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 106</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Yin Ta" sort="Wu, Yin Ta" uniqKey="Wu Y" first="Yin-Ta" last="Wu">Yin-Ta Wu</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Jan, Jia Tsrong" sort="Jan, Jia Tsrong" uniqKey="Jan J" first="Jia-Tsrong" last="Jan">Jia-Tsrong Jan</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institute of Preventive Medicine, National Defense University</s1><s2>Taipei</s2><s3>TWN</s3><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei</wicri:noRegion></affiliation></author><author><name sortKey="Cheng, Yih Shyun E" sort="Cheng, Yih Shyun E" uniqKey="Cheng Y" first="Yih-Shyun E." last="Cheng">Yih-Shyun E. Cheng</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Genomic. Research Center, Academw Sinica</s1><s2>Taipei 115</s2><s3>TWN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 115</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Biological activity</term><term>Chemical synthesis</term><term>Cinnamic acid derivatives</term><term>Enzyme inhibitor</term><term>Ester</term><term>Inhibitor enzyme complex</term><term>Modeling</term><term>Molecular model</term><term>Peptidases</term><term>Peptidomimetic compound</term><term>Protease inhibitor</term><term>Severe acute respiratory syndrome</term><term>Severe acute respiratory syndrome virus</term><term>Vinylic compound</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Synthèse chimique</term><term>Syndrome respiratoire aigu sévère</term><term>Peptidases</term><term>Composé peptidomimétique</term><term>Ester</term><term>Virus syndrome respiratoire aigu sévère</term><term>Activité biologique</term><term>Inhibiteur protease</term><term>Complexe enzyme inhibiteur</term><term>Cinnamique acide dérivé</term><term>Antiviral</term><term>Modèle moléculaire</term><term>Composé vinylique</term><term>Inhibiteur enzyme</term><term>Modélisation</term><term>Phénylalaninamide(N-[1-benzyl-3-éthoxycarbonylallyl]-Nα-[4-(diméthylamino)cinnamoyl])</term><term>Phénylalanine dérivé</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide α,β-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC<sub>50</sub> > 100 μM), the ketomethylene isosteres and tripeptide α,β-unsaturated esters containing both P1 and P<sup>2</sup> phenylalanine residues show modest inhibitory activity (IC<sub>50</sub> = 11-39 μM). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 μM is obtained by condensation of the Phe-Phe dipeptide α,β-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC<sub>50</sub> value of 0.18 μM.</div></front></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><country name="Taïwan"><noRegion><name sortKey="Shie, Jiun Jie" sort="Shie, Jiun Jie" uniqKey="Shie J" first="Jiun-Jie" last="Shie">Jiun-Jie Shie</name></noRegion><name sortKey="Cheng, Yih Shyun E" sort="Cheng, Yih Shyun E" uniqKey="Cheng Y" first="Yih-Shyun E." last="Cheng">Yih-Shyun E. Cheng</name><name sortKey="Fang, Jim Min" sort="Fang, Jim Min" uniqKey="Fang J" first="Jim-Min" last="Fang">Jim-Min Fang</name><name sortKey="Fang, Jim Min" sort="Fang, Jim Min" uniqKey="Fang J" first="Jim-Min" last="Fang">Jim-Min Fang</name><name sortKey="Huang, Hung Jyun" sort="Huang, Hung Jyun" uniqKey="Huang H" first="Hung-Jyun" last="Huang">Hung-Jyun Huang</name><name sortKey="Jan, Jia Tsrong" sort="Jan, Jia Tsrong" uniqKey="Jan J" first="Jia-Tsrong" last="Jan">Jia-Tsrong Jan</name><name sortKey="Kuo, Chih Jung" sort="Kuo, Chih Jung" uniqKey="Kuo C" first="Chih-Jung" last="Kuo">Chih-Jung Kuo</name><name sortKey="Kuo, Tun Hsun" sort="Kuo, Tun Hsun" uniqKey="Kuo T" first="Tun-Hsun" last="Kuo">Tun-Hsun Kuo</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><name sortKey="Wu, Yin Ta" sort="Wu, Yin Ta" uniqKey="Wu Y" first="Yin-Ta" last="Wu">Yin-Ta Wu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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