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Solid-Phase Library Synthesis, Screening, and Selection of Tight-Binding Reduced Peptide Bond Inhibitors of a Recombinant Leishmania m exicana Cysteine Protease B

2002; American Chemical Society; Volume: 45; Issue: 10 Linguagem: Inglês

10.1021/jm0110901

1520-4804

Phaedria M. St. Hilaire, Lira C. Alves, Fatima Herrera, Manat Renil, Sanya J. Sanderson, Jeremy C. Mottram, Graham H. Coombs, María A. Juliano, Luiz Juliano, Jorge Arévalo, Morten Meldal,

Chemical Synthesis and Analysis

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, CPB2.8ΔCTE. 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 P2, Phe in P1, Cha and Ile/Leu in P1', and Ile/Leu in P2'. Some of the inhibitors were resynthesized, and the kinetics of inhibition were determined in solution-phase assays. Most of the inhibitors had micromolar Ki values, and a few inhibited the enzyme at nanomolar concentrations. One inhibitor, DKHF(CH2NH)LLVK (Ki = 1 μM), was tested for antiparasite efficacy and shown to affect parasite survival with an IC50 of approximately 50 μΜ.