title: Trypanocidal activities of trileucine methyl vinyl sulfone proteasome inhibitors.
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.
authors.affiliation: School of Biological Sciences, University of Bristol, Woodland Road, Bristol, BS8 1UG, UK. dsteverding@hotmail.com
authors.forename: Dietmar
authors.initials: D
authors.lastname: Steverding
authors.forename: Robert W
authors.initials: RW
authors.lastname: Spackman
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Royle
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Glenn
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013450:Sulfones; D014344:Trypanocidal Agents; D014361:Trypsin Inhibitors; C011545:semen liquefaction factor; C060916:methyl vinyl sulfone; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C036671:leucyl-leucyl-leucine