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

• Published in: Journal of medicinal chemistry 2002-05, Vol.45 (10), p.1971-1982
• Main Authors: St. Hilaire, Phaedria M, Alves, Lira C, Herrera, Fatima, Renil, Manat, Sanderson, Sanya J, Mottram, Jeremy C, Coombs, Graham H, Juliano, Maria A, Juliano, Luiz, Arevalo, Jorge, Meldal, Morten
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0110901

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 K i values, and a few inhibited the enzyme at nanomolar concentrations. One inhibitor, DKHF(CH2NH)LLVK (K i = 1 μM), was tested for antiparasite efficacy and shown to affect parasite survival with an IC50 of approximately 50 μΜ.