Journal of Medicinal Chemistry 2002-05-09

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

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

Index: J. Med. Chem. 45(10) , 1971-82, (2002)

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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(CH(2)NH)LLVK (K(i) = 1 microm), was tested for antiparasite efficacy and shown to affect parasite survival with an IC(50) of approximately 50 microm.