Four beta-lactone-gamma-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities IN VITRO using culture-adapted bloodstream forms of TRYPANOSOMA BRUCEI. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50?% growth inhibition (GI (50)) values of around 3 nM were the bromine and iodine analogues of salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete SALINISPORA TROPICA. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of beta-lactone-gamma-lactam proteasome inhibitors for rational anti-trypanosomal drug development.