The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate
Family 18 chitinases are attractive targets for the development of new inhibitors with chemotherapeutic potential against fungi, insects and protozoan/nematodal parasites. Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based...
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| Veröffentlicht in: | Biochemical journal 2002-11, Vol.368 (Pt 1), p.23-27 |
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| container_end_page | 27 |
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| container_issue | Pt 1 |
| container_start_page | 23 |
| container_title | Biochemical journal |
| container_volume | 368 |
| creator | Houston, Douglas R Eggleston, Ian Synstad, Bjørnar Eijsink, Vincent G H van Aalten, Daan M F |
| description | Family 18 chitinases are attractive targets for the development of new inhibitors with chemotherapeutic potential against fungi, insects and protozoan/nematodal parasites. Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. The structure reveals that the cyclic dipeptide inhibits chitinases by structurally mimicking a reaction intermediate, and could, on the basis of its accessible chemistry, be a candidate for further optimization. |
| doi_str_mv | 10.1042/bj20021034 |
| format | Article |
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Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. 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Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. The structure reveals that the cyclic dipeptide inhibits chitinases by structurally mimicking a reaction intermediate, and could, on the basis of its accessible chemistry, be a candidate for further optimization.</description><subject>Acetylglucosamine - analogs & derivatives</subject><subject>Acetylglucosamine - chemistry</subject><subject>Acetylglucosamine - pharmacology</subject><subject>Binding Sites</subject><subject>Chitinases - antagonists & inhibitors</subject><subject>Chitinases - chemistry</subject><subject>Chitinases - genetics</subject><subject>Molecular Conformation</subject><subject>Molecular Mimicry</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Plant Proteins - antagonists & inhibitors</subject><subject>Plant Proteins - chemistry</subject><subject>Plant Proteins - genetics</subject><subject>Protein Conformation</subject><subject>Protein Engineering</subject><subject>Serratia marcescens - enzymology</subject><subject>Trisaccharides - chemistry</subject><subject>Trisaccharides - pharmacology</subject><subject>X-Ray Diffraction</subject><issn>0264-6021</issn><issn>1470-8728</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtrFEEUhQtRzCS68QdIrcQIFW89erpmI4TBRyCQLOJKpKhXZ27o7hqrqoXe-NvTIYPR1YV7Ps45cAh5w-GMgxIf3Z0AEBykekZWXLXAdCv0c7ICsVZsvUhH5LiUOwCuQMFLcsSFFBJatSJ_bnaR-tn36GnAfdxXDJFuL5iiPx7eib3v2Xm-ZYFd53T6k-K4Q4e10M4O2M-Ua-p3WHG0JRbqZlpqnnydsu3pgAP6PNPUUUtztL5iGheHGvMQA9oaX5EXne1LfH24J-T7l88322_s8urrxfb8knmloDLOdWhBOdtJ4BC867zz0GodQtDaw8Y2UQbnO-eaJqy5DVop3wkH0EanuTwhnx5995Nbon0c61LQ7DMONs8mWTT_KyPuzG36bbgQYrOBxeDdwSCnX1Ms1QxYfOx7O8Y0FdOKdSMbqRfwwyPocyolx-5vCAfzMJd5mmuB3_5b6wk97CPvAdBPkmc</recordid><startdate>20021115</startdate><enddate>20021115</enddate><creator>Houston, Douglas R</creator><creator>Eggleston, Ian</creator><creator>Synstad, Bjørnar</creator><creator>Eijsink, Vincent G H</creator><creator>van Aalten, Daan M F</creator><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><scope>5PM</scope></search><sort><creationdate>20021115</creationdate><title>The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate</title><author>Houston, Douglas R ; Eggleston, Ian ; Synstad, Bjørnar ; Eijsink, Vincent G H ; van Aalten, Daan M F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c440t-118d704baf3010dcbfcbc0788ddd88c09a5e3dbcfbb55d61ad844cf2b007eb813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Acetylglucosamine - analogs & derivatives</topic><topic>Acetylglucosamine - chemistry</topic><topic>Acetylglucosamine - pharmacology</topic><topic>Binding Sites</topic><topic>Chitinases - antagonists & inhibitors</topic><topic>Chitinases - chemistry</topic><topic>Chitinases - genetics</topic><topic>Molecular Conformation</topic><topic>Molecular Mimicry</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Plant Proteins - antagonists & inhibitors</topic><topic>Plant Proteins - chemistry</topic><topic>Plant Proteins - genetics</topic><topic>Protein Conformation</topic><topic>Protein Engineering</topic><topic>Serratia marcescens - enzymology</topic><topic>Trisaccharides - chemistry</topic><topic>Trisaccharides - pharmacology</topic><topic>X-Ray Diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Houston, Douglas R</creatorcontrib><creatorcontrib>Eggleston, Ian</creatorcontrib><creatorcontrib>Synstad, Bjørnar</creatorcontrib><creatorcontrib>Eijsink, Vincent G H</creatorcontrib><creatorcontrib>van Aalten, Daan M F</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Houston, Douglas R</au><au>Eggleston, Ian</au><au>Synstad, Bjørnar</au><au>Eijsink, Vincent G H</au><au>van Aalten, Daan M F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate</atitle><jtitle>Biochemical journal</jtitle><addtitle>Biochem J</addtitle><date>2002-11-15</date><risdate>2002</risdate><volume>368</volume><issue>Pt 1</issue><spage>23</spage><epage>27</epage><pages>23-27</pages><issn>0264-6021</issn><eissn>1470-8728</eissn><abstract>Family 18 chitinases are attractive targets for the development of new inhibitors with chemotherapeutic potential against fungi, insects and protozoan/nematodal parasites. Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. The structure reveals that the cyclic dipeptide inhibits chitinases by structurally mimicking a reaction intermediate, and could, on the basis of its accessible chemistry, be a candidate for further optimization.</abstract><cop>England</cop><pmid>12323074</pmid><doi>10.1042/bj20021034</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Acetylglucosamine - analogs & derivatives Acetylglucosamine - chemistry Acetylglucosamine - pharmacology Binding Sites Chitinases - antagonists & inhibitors Chitinases - chemistry Chitinases - genetics Molecular Conformation Molecular Mimicry Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Plant Proteins - antagonists & inhibitors Plant Proteins - chemistry Plant Proteins - genetics Protein Conformation Protein Engineering Serratia marcescens - enzymology Trisaccharides - chemistry Trisaccharides - pharmacology X-Ray Diffraction |
| title | The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate |
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