Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B
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2002-05-09
Authors
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.
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Abstract
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.
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Journal of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 45, n. 10, p. 1971-1982, 2002.