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

St. Hilaire, P.M. et al. (2002) Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B. Journal of Medicinal Chemistry, 45, pp. 1971-1982. (doi: 10.1021/jm0110901)

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, CPB2.8ΔCTE. 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coombs, Professor Graham and Mottram, Professor Jeremy
• Authors: St. Hilaire, P.M., Alves, L.C., Herrera, F., Renil, M., Sanderson, S.J., Mottram, J.C., Coombs, G.H., Juliano, M.A., Juliano, L., Arevalo, J., and Meldal, M.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 03 April 2002