Trypanocidal activities of trileucine methyl vinyl sulfone proteasome inhibitors.

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.