The infections caused by parasitic protozoa place a severe burden of illness in the World's population. Many of these infections, although not directly fatal, induce extreme morbidity in infected individuals. Current regimens for the treatment of the majority of these diseases are dogged by recurring problems of drug toxicity and side effects, and widespread development of drug-resistance with a restricted spectrum of active compounds. These problems can only intensify therefore it is vital that new targets and novel compounds be developed into antiparasite drugs as soon as possible. This current Program application entitled """"""""Exploitation of Novel Drug Targets in Protozoal Infections"""""""" proposes to address these specific problems for malaria, leishmaniasis and amebiasis. The projects show a high degree of unity based on mutually complementary skills, shared goals, and a preexisting interaction between the 4 individual laboratories. All projects propose to target enzymes that have already been identified and show activities that are specific to the parasite. Project 1 has two complementary aims; The exploitation of macrophage-restricted receptors to target active compounds to the endocytic network of Leishmania-infected macrophages, and the development of substrates specific to the parasite's cysteine proteinases as inhibitors of enzyme activity. These activities are required for the growth of axenic amastigotes in culture. Project 2 exploits the requirement for the aspartic hemoglobinase in the degradation of host erythrocyte hemoglobin by the parasite Plasmodium falciparum. To develop a new antimalarials, this project proposes to improve on peptidomimetic inhibitors that have been shown to block parasite growth in culture. Project 3 is aimed analyzing the interactions between the Entameba histolytica cysteine proteinases, which are fundamental to the pathology of invasive amebiasis, with laminin. The investigators propose to identify the region(s) of laminin involved in the tight binding with amebal proteinases to facilitate development of Entameba-specific proteinase inhibitors. Project 4 targets a vital bifunctional alcohol dehydrogenase/acetyl coA reductase, unique to Entameba histolytica, as a novel site a drug action. Sequence analysis of the enzyme reveals homology only with anaerobic prokaryote enzymes suggesting that the alcohol dehydrogenase/acetyl coA reductase will be a specific target. Together these projects combine to exploit the common interest of the Project Leaders and make most efficient use of their broad experience in the diverse disciplines required for effective drug development.
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