My research concentrates on drug discovery for diseases caused by a variety of pathogenic protozoa. These include Trypanosoma cruzi (the cause of Chagas disease), Trypanosoma brucei (the cause of African sleeping sickness), Leishmania species (the cause of leishmaniasis), and Plasmodium falciparum (the cause of malignant malaria). I am principally focusing on two biochemical targets for developing antiparasitic drugs: sterol biosynthesis and protein prenylation. The general approach is to use molecular biology techniques to study enzymes involved in these pathways. This requires the molecular cloning and heterologous expression of these proteins. The enzymes are then characterized functionally and in some cases subjected to structural analysis by X-ray crystallography. The 3-dimensional structures are used to model molecules that can serve as enzyme inhibitors. The molecular, parasitology, and biochemistry work are conducted in my laboratory. The X-ray crystallography and computer modeling work is done in collaboration with Dr. Wim Hol and Dr. Christophe Verlinde (Dept. of Biochemistry). Organic synthesis of inhibitors is done by Dr. Michael Gelb's group in the Dept. of Chemistry. Inhibitors are tested for in vitro activity against enzyme targets and against the parasites grown in culture. Leads are refined by molecular modeling approaches (rational drug design). The compounds with the best antiparasitic activity and least toxicity to mammalian cells undergo testing in mouse models of these infectious diseases. Our group represents one of the few collaborative efforts in the world dedicated to rational drug discovery for tropical pathogenic protozoa.