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Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors—Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases)

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. 7192-7210
Number 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

Number of the records: 1