The Neddylation Pathway in Leishmania donovani - A High Opportunity Target

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Leishmania and other kinetoplastid parasites cause devastating diseases that afflict millions of people, and L. donovani typically causes fatal visceral leishmaniasis. Because current drug regimens are woefully inadequate, it is important to identify specific targets that can be exploited for development of novel orally bioavailable drugs that will improve therapeutic options. The neddylation pathway in these parasites represents a high opportunity target with multiple enzymes that are likely essential for survival of intracellular disease-causing parasites. This pathway uses specific E1, E2, and E3 activating enzymes to attach the small ubiquitin -like protein, NEDD8, onto various cellular substrates, such as the cullin ligases that are important components of the essential ubiquitination pathway. Neddylation of these substrates typically activates their functions and thus regulates the relevant downstream pathway. Significantly, each of 3 neddylation enzymes has already been targeted for development of anti-cancer drugs in humans, with one experimental drug undergoing phase 3 clinical trials. These successes indicate that each enzyme is druggable and that parallel studies on the orthologous but highly sequence divergent enzymes from L. donovani is likely to identify parasite-specific drug- like inhibitors that will inactivate the neddylation pathway with lethal effects for the parasite but with minimal effects on host cells. The purpose of this project is to delete in L. donovani each of the 3 genes for these enzymes, called UBA3, DCN1, and CSN5, and determine whether such deletions strongly impair growth of the intracellular disease-causing stage of the parasite life cycle. Successful demonstration of essentiality for some or all of these neddylation enzymes will validate them as drug targets whose inhibition by parasite-selective small molecules would provide novel therapeutic modalities for this burdensome global infectious disease. These results will provide the impetus for a subsequent drug development program to target this pathway. In addition, phenotypic studies on the null mutants will reveal important biological processes governed by the neddylation pathway and will thus provide powerful insights into the basic biology of this pathogen.