Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B

Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B

Autor Hilaire, PMS Google Scholar
Alves, L. C. Google Scholar
Herrera, F. Google Scholar
Renil, M. Google Scholar
Sanderson, S. J. Google Scholar
Mottram, J. C. Google Scholar
Coombs, G. H. Google Scholar
Juliano, M. A. Google Scholar
Juliano, L. Google Scholar
Arevalo, J. Google Scholar
Meldal, M. Google Scholar
Instituição Carlsberg Lab
Universidade Federal de São Paulo (UNIFESP)
Univ Peruana Cayetano Heredia
Univ Glasgow
Resumo A one-bead-two-compound inhibitor library was synthesized by the split-mix method for the identification of inhibitors of a recombinant cysteine protease from Leishmania mexicana, CPB2.8DeltaCTE. the inhibitor library was composed of octapeptides with a centrally located reduced bond introduced by reductive amination of the resin-bound amines with Fmoc amino aldehydes. the library was screened on solid phase, and less than 1% of the library contained active compounds. the inhibitors displayed great specificity in the subsites flanking the enzyme catalytic triad with Cha and Ile/Leu preferred in P-2, Phe in P-1, Cha and Ile/Leu in P-1', and Ile/Leu in P-2'. Some of the inhibitors were resynthesized, and the kinetics of inhibition were determined in solution-phase assays. Most of the inhibitors had micromolar K-i values, and a few inhibited the enzyme at nanomolar concentrations. One inhibitor, DKHF(CH2NH)LLVK (K-i = 1 muM), was tested for antiparasite efficacy and shown to affect parasite survival with an IC50 of approximately 50 muM.
Idioma Inglês
Data de publicação 2002-05-09
Publicado em Journal of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 45, n. 10, p. 1971-1982, 2002.
ISSN 0022-2623 (Sherpa/Romeo, fator de impacto)
Publicador Amer Chemical Soc
Extensão 1971-1982
Fonte http://dx.doi.org/10.1021/jm0110901
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000175488900004
Endereço permanente http://repositorio.unifesp.br/handle/11600/26870

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