Prospects for antiparasitic drugs. The case of Trypanosoma brucei, the causative agent of African sleeping sickness.
Glycolysis in the bloodstream form of Trypanosoma brucei provides a convenient context for studying the prospects for using enzyme inhibitors as antiparasitic drugs. As the recently developed model of this system (Bakker, B. M., Michels, P. A. M., Opperdoes, F. R., and Westerhoff, H. V. (1997) J. Biol. Chem. 272, 3207-3215) contains 20 enzyme-catalyzed reactions or transport steps, there are apparently numerous potential targets for drugs. However, as most flux control resides in the glucose-transport step, this is the only step for which inhibition can be expected to produce large effects on flux, and in the computer model such effects prove to be surprisingly small (although larger than those obtained by inhibiting any other step). It follows that there is little prospect of killing trypanosomes by depressing their glycolysis to a level incapable of sustaining life. The alternative is to use inhibition to increase the concentration of a metabolite sufficiently to interfere with the viability of the organism. For this purpose, only uncompetitive inhibition of pyruvate export proves effective in the model; in all other cases studied, the effects on metabolite concentrations are little more than trivial. This observation can be explained by the fact that nearly all of the metabolite concentrations in the system are held within relatively narrow ranges by stoichiometric constraints.
Eisenthal
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Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom. bssre@bath.ac.uk
Cornish-Bowden
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D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000493:pharmacokinetics; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000037:antagonists & inhibitors; D007700:Kinetics; D019289:Pyruvic Acid / Q000493:pharmacokinetics; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism
D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D019289:Pyruvic Acid; D006593:Hexokinase; D005947:Glucose