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 method for the prophylaxis and treatment of these diseases are less than satisfactory. Sterols are essential components of eucaryotic cell membranes. The principal sterol of human tissues is cholesterol, but ergosterol is the major sterol biosynthesized by parasitic protozoa. If de novo sterol biosynthesis is required for the growth of the Trypanosomatidae, then the ergosterol biosynthetic pathway should contain several enzymes which would be appropriate targets for rationally designed antiparasitic agents. We propose to develop specific inhibitors of the enzymes which elaborate the sterol side chain in erogosterol biosynthesis. These enzymes have no counterpart in mammalian cholesterol biosynthesis, and thus their inhibition should halt protozoan sterol synthesis, and presumably protozoan growth, without affecting the mammalian host. Similarly we propose to develop inhibitors of the enzymes involved in the biosynthesis of dihydrosterculic acid, a major cyclopropane-containing fatty acid in the parasitic protozoa but not in humans. We will synthesize a variety of potential inhibitors, the rationales for which are detailed in this proposal, and test their effects on lipid biosynthesis and growth of the non-pathogenic protozoan Crithidia fasciculata, a close biochemical relative of the human pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI024146-01
Application #
3136865
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1987-01-01
Project End
1989-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Princeton University
Department
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Rahman, M D; Pascal Jr, R A (1990) Inhibitors of ergosterol biosynthesis and growth of the trypanosomatid protozoan Crithidia fasciculata. J Biol Chem 265:4989-96
Beach, D H; Pascal Jr, R A; Holz Jr, G G (1989) Effects of thiastearic acids on growth and on dihydrosterculic acid and other phospholipid fatty acyl groups of Leishmania promastigotes. Mol Biochem Parasitol 35:57-66
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