Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei.
(1993) Molecular and Biochemical Parasitology — Vol. 59, n° 2, p. 201-210 (1993)
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- 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.
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Willson, M., Callens, M., Kuntz, D. A., Perié, J., & Opperdoes, F. (1993). Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Molecular and Biochemical Parasitology, 59(2), 201-210. https://doi.org/10.1016/0166-6851(93)90218-M (Original work published 1993)