Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B
Nenhuma Miniatura disponível
Data
2002-05-09
Autores
Hilaire, PMS
Alves, L. C.
Herrera, F.
Renil, M.
Sanderson, S. J.
Mottram, J. C.
Coombs, G. H.
Juliano, M. A.
Juliano, L.
Arevalo, J.
Orientadores
Tipo
Artigo
Título da Revista
ISSN da Revista
Título de Volume
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.
Descrição
Citação
Journal of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 45, n. 10, p. 1971-1982, 2002.