title: Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei.
abstract: Most glycosomal enzymes of Trypanosoma brucei carry a relatively high number of positive charges. In at least 3 of the enzymes some of the charges unique to these enzymes are concentrated in 2 distinct areas on the enzymes' surface, about 4 nm apart [4] and these positively charged structural elements have been suggested to be the site of interaction with the trypanocidal drug Suramin. We have synthesized a series of symmetrical long chain molecules with negative charges or strong dipoles at each end. Several of these compounds inhibited the glycosomal enzymes more strongly than Suramin. They also exhibited a specificity for the trypanosome enzymes, when compared with homologous enzymes from other organisms. By varying the chain length of the active compounds, a 4-nm distance between the molecules' extremes proved optimal for inhibition. Tetra-substituted compounds were better than di-substituted. Modifications introduced at the two ends indicated that a planar orientation, with an amide bond linking a phenyl ring to the chain, is preferred. Inhibition kinetics for some of the enzymes indicated the existence of multi-site interactions with the inhibitors.
authors.affiliation: Groupe de Chimie Organique Biologique (URA au CNRS 470), Université Paul Sabatier, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Willson
authors.forename: M
authors.initials: M
authors.lastname: Callens
authors.forename: D A
authors.initials: DA
authors.lastname: Kuntz
authors.forename: J
authors.initials: J
authors.lastname: Perié
authors.forename: F R
authors.initials: FR
authors.lastname: Opperdoes
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D013498:Suramin / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D001565:Benzoates; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D013498:Suramin