Počet záznamů: 1

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

  1. 1.
    0335281 - BC-A 2010 RIV US eng J - Článek v odborném periodiku
    Ovat, A. - Muindi, F. - Fagan, C. - Brouner, M. - Hansell, E. - Dvořák, J. - Sojka, Daniel - Kopáček, Petr - McKerrow, J. H. - Caffrey, C. R. - Powers, J. C.
    Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors—Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases).
    Journal of Medicinal Chemistry. Roč. 52, č. 22 (2009), s. 7192-7210 ISSN 0022-2623
    Grant CEP: GA ČR GA206/06/0865; GA MŠk(CZ) LC06009
    Výzkumný záměr: CEZ:AV0Z60220518
    Klíčová slova: legumain * IrAE * aza-peptide Michael acceptors
    Kód oboru RIV: EC - Imunologie
    Impakt faktor: 4.802, rok: 2009

    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.
    Trvalý link: http://hdl.handle.net/11104/0179788