A library of 121 pseudopeptides was designed to develop reversible inhibito
rs of trypanosomal enzymes (cruzain from Trypanosoma cruzi and congopain fr
om Trypanosoma congolense). The peptides share the framework: Cha-X1-X2-Pro
(Cha = cyclohexyl-alanine, X1 and X2 were phenylalanyl analogs), based on
a previous report [Lecaille, F., Authie, E., Moreau, T., Serveau, C., Gauth
ier, F. and Lalmanach, G. (2001) Eur. J. Biochem. 268, 2733-2741]. Five pep
tides containing a nitro-substituted aromatic residue (Tyr/Phe) and one a 4
-chlorophenylalanine at the X1 position, and 3-(2-naphthyl)-alanine, homocy
clohexylalanine or 3-nitro-tyrosine (3-NO2-Tyr) at the X2 position, were se
lected. They inhibited congopain more effectively than cruzain, except Cha4
-NO2-Phe-3-NO2-Tyr-Pro which bound the two parasitic enzymes similarly. Amo
ng this series, Cha-3-NO2-Tyr-HoCha-Pro and Cha-4-NO2-Phe-3-NO2-Tyr-Pro are
the most selective for congopain relative to host cathepsins. No hydrolysi
s occurred upon prolonged incubation time with purified enzymes. In additio
n introduction of non-proteogenic residues in the peptidyl backbone greatly
enhanced resistance to proteolysis by mammalian sera. (C) 2001 Federation
of European Biochemical Societies. Published by Elsevier Science B.V. All r
ights reserved.