Using Metabolic Control Analysis To Improve The Selectivity and Effectiveness of Drugs Against Parasitic Diseases

Abstract

Trypanosoma brucei is the parasite that causes African sleeping sickness in humans and the related disease nagana in cattle. The development of drugs is hampered by the many similarities between this parasite and the cells of its host. Until now advanced drug-design strategies have focussed on the differences between the three-dimensional structure of trypanosome and human enzymes (Verlinde & Hol, 1994). We propose that the selectivity of a drug can be further enhanced by choosing a target enzyme with a high flux control coefficient in the parasite and a low flux control coefficient in the host cells. Trypanosome glycolysis is a very suitable model system for this approach. In the mammalian bloodstream T. brucei depends completely on glycolysis (Michels, 1988). In many of its host cells glycolysis is also essential. The organization of this pathway and the regulation of its enzymes differ greatly between the two organisms (Michels, 1988). Most conspicuously, in trypanosomes part of glycolysis takes place in specialized organelles (glycosomes), whereas in the host the corresponding pathway is localized in the cytosol. In view of this and other differ-ences there is a fair chance that the distributrion of the control of the glycolytic flux over the glycolytic enzymes will also be different.