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Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors—Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases)
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SYSNO ASEP 0335281 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors—Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases) Author(s) Ovat, A. (US)
Muindi, F. (US)
Fagan, C. (US)
Brouner, M. (US)
Hansell, E. (US)
Dvořák, J. (US)
Sojka, Daniel (BC-A) RID, ORCID
Kopáček, Petr (BC-A) RID, ORCID
McKerrow, J. H. (US)
Caffrey, C. R. (US)
Powers, J. C. (US)Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 52, č. 22 (2009), s. 7192-7210Number of pages 19 s. Language eng - English Country US - United States Keywords legumain ; IrAE ; aza-peptide Michael acceptors Subject RIV EC - Immunology R&D Projects GA206/06/0865 GA ČR - Czech Science Foundation (CSF) LC06009 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) CEZ AV0Z60220518 - PAU-O, BC-A (2005-2011) UT WOS 000271825600024 DOI 10.1021/jm900849h Annotation Aza-peptide Michael acceptors and epoxides with the general structure of YCO-Ala-Ala-AAsn-trans-CHdCHCOR are shown to be potent inhibitors of asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE), and the hard tick, Ixodes ricinus (IrAE). Structure-activity relationships (SARs) were determined for a set of 41 aza-peptide Michael acceptors and 8 aza-peptide epoxides. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1 position. Extending the inhibitor to P5 resulted in increased potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues at P2. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors, and for some of these compounds, second-order inhibiton rate constants are the fastest yet discovered. Given the central functions of these enzymes in both parasites, the data presented here may facilitate the eventual design of selective antiparasitic drugs. Workplace Biology Centre (since 2006) Contact Dana Hypšová, eje@eje.cz, Tel.: 387 775 214 Year of Publishing 2010
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