Parasitic protozoa of the family Trypanosomatidae are the causative agents of several tropical diseases including African sleeping sickness, Chagas' disease of Central and South America, and the various leishmaniases of the New and Old Worlds. Unfortunately, chemotherapeutic methods for the prophylaxis and treatment of these diseases are less than satisfactory. Sterols are essential components of eucaryotic membranes. The principal sterol of human tissues is cholesterol, but ergosterol is the major sterol biosynthesized by parasitic protozoa. Special inhibitors of the enzymes which elaborate the sterol side chain in ergosterol biosynthesis will be developed. These enzymes have no counterpart in mammalian cholesterol biosynthesis, so inhibitors of these enzymes should halt protozoan sterol synthesis and growth without affecting a mammalian host. The trypanosomatids also contains numerous polyunsaturated and branched-chain fatty acids, some with structures unique to these parasites. Specific inhibitors of key enzymes in protozoan fatty acid biosynthesis will be developed. Special emphasis will be placed on the inhibition of (1) reactions with no counterparts in mammals and (2) reactions similar to those in mammals which are, however, catalyzed by very different enzymes. The research plan will involve (1) organic synthesis of potential inhibitors, (2) testing of these compounds for effects on lipid distribution and growth in Crithidia fasciculata (a) non- pathogenic protozoan which is a very close biochemical relative of the human pathogens), (3) examination of the metabolic processing of promising compounds, (4) determination of the specific sites of inhibition by these compounds or their metabolites in cell-free systems. Active compounds will be submitted for testing in pathogenic varieties of trypanosomatids with a collaborator.
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| Rahman, M D; Ziering, D L; Mannarelli, S J et al. (1988) Effects of sulfur-containing analogues of stearic acid on growth and fatty acid biosynthesis in the protozoan Crithidia fasciculata. J Med Chem 31:1656-9 |
| Rahman, M D; Seidel, H M; Pascal Jr, R A (1988) Synthesis of 24-heteroatom-substituted cholestanols. J Lipid Res 29:1543-8 |
