Trypanocidal Activity of β-Lactone-γ-Lactam Proteasome Inhibitors

Abstract

Four β-lactone-γ-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 (GI₅₀) 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 β-lactone-γ-lactam proteasome inhibitors for rational anti-trypanosomal drug development.

Key words

Trypanosoma brucei - sleeping sickness - β-lactone-γ-lactam proteasome inhibitors - trypanocidals

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