No abstract

Previous studies have shown that proteasome inhibitors are novel agents for chemotherapy of human African trypanosomiasis or sleeping sickness. In this study, five peptide trileucine methyl vinyl sulfones with different N-terminal substituents were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. Two inhibitors displayed promising anti-trypanosomal activities with ED50 values in the sub-micromolar range. Higher trypanocidal activity of the compounds generally corresponded to a higher k(obs)/[I] value for inhibition of the trypsin-like activity but not for the inhibition of the chymotrypsin-like activity of the proteasome. These data suggest that inhibitors with strong activity against the trypsin-like activity of the proteasome are the rational choice for future anti-sleeping sickness drug development.

The natural compound tyropeptin A, a new peptidyl aldehyde proteasome inhibitor, was tested for its trypanocidal activity in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. The concentrations of tyropeptin A required to reduce the growth rate by 50 % and to kill all cells were 10 and 100 times lower for bloodstream-form trypanosomes than for human leukaemia HL-60 cells, respectively. Enzymatic analysis showed that the trypsin-like activity of the trypanosome proteasome and the chymotrypsin-like activity of the mammalian proteasome are particularly sensitive to inhibition by tyropeptin A. The results suggest that natural compounds targeting the trypsin-like activity of the proteasome may serve as leads for rational drug development of novel anti-trypanosomal agents.