Inhibition of cruzipain visualized in a fluorescence quenched solid-phase inhibitor library assay. D-amino acid inhibitors for cruzipain, cathepsin B and cathepsin L

Inhibition of cruzipain visualized in a fluorescence quenched solid-phase inhibitor library assay. D-amino acid inhibitors for cruzipain, cathepsin B and cathepsin L

Autor Meldal, M. Google Scholar
Svendsen, I Google Scholar
Juliano, L. Google Scholar
Juliano, M. A. Google Scholar
Del Nery, E. Google Scholar
Scharfstein, J. Google Scholar
Instituição Carlsberg Lab
Universidade Federal de São Paulo (UNIFESP)
Universidade Federal do Rio de Janeiro (UFRJ)
Resumo A PEGA-resin was derivatized with a 3:1 mixture of hydroymethyl benzoic acid and Fmoc-Lys(Boc)-OH and the fluorogenic substrate Ac-Y(NO2)KLRFSKQK(Abz)-PEGA was assembled on the lysine using the active ester approach. Following esterification of the hydroxymethyl benzoic acid with Fmoc-Val-OH a library XXX-k/r-XXXV containing approximately 200,000 beads was assembled by split synthesis. the resulting 'one bead, two peptides' library was subjected to extensive hydrolysis with cruzipain. One hundred darker beads were isolated and the 14 most persistently dark beads were collected and sequenced. the putative inhibitor peptides and several analogues were synthesized and found to be competitive mu M to nM inhibitors of cruzipain in solution. the inhibitory activity was found to be unspecific to cruzipain when compared with cathepsins B and L and specific when compared with kallikrein. One of the inhibitors was docked into the active site of cathepsin B and was found most probably to bind to the enzyme cavity in an unusual manner, owing to the inserted D-amino acid residue. (C) 1998 European Peptide Society and John Wiley & Sons, Ltd.
Palavra-chave fluorescence quenched assay
inhibitor library
Trypanosoma cruzi
cathepsin B and L inhibitors
parasitic protease inhibition
Idioma Inglês
Data de publicação 1998-04-01
Publicado em Journal of Peptide Science. W Sussex: John Wiley & Sons Ltd, v. 4, n. 2, p. 83-91, 1998.
ISSN 1075-2617 (Sherpa/Romeo, fator de impacto)
Publicador Wiley-Blackwell
Extensão 83-91
Fonte http://dx.doi.org/10.1002/(SICI)1099-1387(199804)4:2<83
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000073108900001
Endereço permanente http://repositorio.unifesp.br/handle/11600/25882

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