Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8
Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1....
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| Veröffentlicht in: | Journal of medicinal chemistry 2004-03, Vol.47 (6), p.1553-1574 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 47 |
| creator | James, Karen Ellis Asgian, Juliana L Li, Zhao Zhao Ekici, Özlem Doǧan Rubin, John R Mikolajczyk, Jowita Salvesen, Guy S Powers, James C |
| description | Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD). |
| doi_str_mv | 10.1021/jm0305016 |
| format | Article |
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Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0305016</identifier><identifier>PMID: 14998341</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Aza Compounds - chemical synthesis ; Aza Compounds - chemistry ; Biological and medical sciences ; Caspase 1 - chemistry ; Caspase 3 ; Caspase 6 ; Caspase 8 ; Caspase Inhibitors ; Caspases - chemistry ; Crystallography, X-Ray ; Drug Design ; Drug Stability ; Epoxy Compounds - chemical synthesis ; Epoxy Compounds - chemistry ; Humans ; Hydrolysis ; Medical sciences ; Miscellaneous ; Molecular Structure ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Pharmacology. Drug treatments ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2004-03, Vol.47 (6), p.1553-1574</ispartof><rights>Copyright © 2004 American Chemical Society</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-7aed4edff4731371a6073b87c9f0f74cc2abb98d08d848449b35625b85c717af3</citedby><cites>FETCH-LOGICAL-a445t-7aed4edff4731371a6073b87c9f0f74cc2abb98d08d848449b35625b85c717af3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm0305016$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0305016$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15566016$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14998341$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>James, Karen Ellis</creatorcontrib><creatorcontrib>Asgian, Juliana L</creatorcontrib><creatorcontrib>Li, Zhao Zhao</creatorcontrib><creatorcontrib>Ekici, Özlem Doǧan</creatorcontrib><creatorcontrib>Rubin, John R</creatorcontrib><creatorcontrib>Mikolajczyk, Jowita</creatorcontrib><creatorcontrib>Salvesen, Guy S</creatorcontrib><creatorcontrib>Powers, James C</creatorcontrib><title>Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).</description><subject>Aza Compounds - chemical synthesis</subject><subject>Aza Compounds - chemistry</subject><subject>Biological and medical sciences</subject><subject>Caspase 1 - chemistry</subject><subject>Caspase 3</subject><subject>Caspase 6</subject><subject>Caspase 8</subject><subject>Caspase Inhibitors</subject><subject>Caspases - chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Drug Stability</subject><subject>Epoxy Compounds - chemical synthesis</subject><subject>Epoxy Compounds - chemistry</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Molecular Structure</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Pharmacology. Drug treatments</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEFv1DAQhS0EotuWA38A-UKlSmtqx07sHKtlgaJKbLsFcbMmjkO9ZJOQcaq2v56UrLoXDqM30nzzZvQIeSv4B8ETcbbZcslTLrIXZCbShDNluHpJZpwnCUuyRB6QQ8QN51yKRL4mB0LluZFKzMjjR4_hVzOn64cm3o49zik0JV3eQT1ADG1D24qePwJb-S6G0tNl196PihSQrn3tXQx3_t_Oqo2-ifSiuQ1FiG2PT6sLwA7QIxNzyuRY2XSAmWPyqoIa_ZudHpHvn5Y3iy_s8tvni8X5JQOl0sg0-FL5sqqUlkJqARnXsjDa5RWvtHIugaLITclNaZRRKi9kmiVpYVKnhYZKHpGTybfr2z-Dx2i3AZ2va2h8O6DVIsu1lnoETyfQ9S1i7yvb9WEL_YMV3D4FbZ-DHtl3O9Oh2PpyT-6SHYH3OwDQQV310LiAey5Ns2wyYhMXMPr75zn0v202PpXam9Xaiqtro358_Wnl3hcc2k079M2Y3X8e_AsmxZ1v</recordid><startdate>20040311</startdate><enddate>20040311</enddate><creator>James, Karen Ellis</creator><creator>Asgian, Juliana L</creator><creator>Li, Zhao Zhao</creator><creator>Ekici, Özlem Doǧan</creator><creator>Rubin, John R</creator><creator>Mikolajczyk, Jowita</creator><creator>Salvesen, Guy S</creator><creator>Powers, James C</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20040311</creationdate><title>Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8</title><author>James, Karen Ellis ; Asgian, Juliana L ; Li, Zhao Zhao ; Ekici, Özlem Doǧan ; Rubin, John R ; Mikolajczyk, Jowita ; Salvesen, Guy S ; Powers, James C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-7aed4edff4731371a6073b87c9f0f74cc2abb98d08d848449b35625b85c717af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Aza Compounds - chemical synthesis</topic><topic>Aza Compounds - chemistry</topic><topic>Biological and medical sciences</topic><topic>Caspase 1 - chemistry</topic><topic>Caspase 3</topic><topic>Caspase 6</topic><topic>Caspase 8</topic><topic>Caspase Inhibitors</topic><topic>Caspases - chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Drug Stability</topic><topic>Epoxy Compounds - chemical synthesis</topic><topic>Epoxy Compounds - chemistry</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Molecular Structure</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Pharmacology. Drug treatments</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>James, Karen Ellis</creatorcontrib><creatorcontrib>Asgian, Juliana L</creatorcontrib><creatorcontrib>Li, Zhao Zhao</creatorcontrib><creatorcontrib>Ekici, Özlem Doǧan</creatorcontrib><creatorcontrib>Rubin, John R</creatorcontrib><creatorcontrib>Mikolajczyk, Jowita</creatorcontrib><creatorcontrib>Salvesen, Guy S</creatorcontrib><creatorcontrib>Powers, James C</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>James, Karen Ellis</au><au>Asgian, Juliana L</au><au>Li, Zhao Zhao</au><au>Ekici, Özlem Doǧan</au><au>Rubin, John R</au><au>Mikolajczyk, Jowita</au><au>Salvesen, Guy S</au><au>Powers, James C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2004-03-11</date><risdate>2004</risdate><volume>47</volume><issue>6</issue><spage>1553</spage><epage>1574</epage><pages>1553-1574</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>14998341</pmid><doi>10.1021/jm0305016</doi><tpages>22</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2004-03, Vol.47 (6), p.1553-1574 |
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| subjects | Aza Compounds - chemical synthesis Aza Compounds - chemistry Biological and medical sciences Caspase 1 - chemistry Caspase 3 Caspase 6 Caspase 8 Caspase Inhibitors Caspases - chemistry Crystallography, X-Ray Drug Design Drug Stability Epoxy Compounds - chemical synthesis Epoxy Compounds - chemistry Humans Hydrolysis Medical sciences Miscellaneous Molecular Structure Oligopeptides - chemical synthesis Oligopeptides - chemistry Pharmacology. Drug treatments Stereoisomerism Structure-Activity Relationship |
| title | Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8 |
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