SYNTHESIS AND ACTIVITY OF INHIBITORS HIGHLY SPECIFIC FOR THE GLYCOLYTIC-ENZYMES FROM TRYPANOSOMA-BRUCEI

被引:59
作者
WILLSON, M
CALLENS, M
KUNTZ, DA
PERIE, J
OPPERDOES, FR
机构
[1] UNIV TOULOUSE 3,CHIM ORGAN BIOL GRP,CNRS,URA 470,F-31062 TOULOUSE,FRANCE
[2] INT INST CELLULAR & MOLEC PATHOL,TROP DIS RES UNIT,B-1200 BRUSSELS,BELGIUM
关键词
TRYPANOSOMA-BRUCEI; GLYCOLYSIS; GLYCOLYTIC ENZYME; SURAMIN; INHIBITOR;
D O I
10.1016/0166-6851(93)90218-M
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:201 / 210
页数:10
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