Trypanocidal activities of trileucine methyl vinyl sulfone proteasome inhibitors

Dietmar Steverding, Robert W Spackman, Howard J Royle, Robert J Glenn

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)73-76
Number of pages4
JournalParasitology Research
Volume95
Issue number1
Early online date1 Dec 2004
DOIs
Publication statusPublished - Jan 2005

Keywords

  • Animals
  • Drug Evaluation, Preclinical
  • Oligopeptides
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors
  • Sulfones
  • Trypanocidal Agents
  • Trypanosoma brucei brucei
  • Trypsin Inhibitors

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