Functional Genomic Approach to Macrofilaricide Discovery

DESCRIPTION (provided by applicant): Parasitic filarial nematodes causing lymphatic filariasis and river blindness (onchocerciasis), infect over 140 million people with up to one billion at risk in at least 80 countries and territories. Lymphatic filariasis (caused by Wuchereria and Brugia species) creates an enormous health and economic burden within affected areas and is ranked as the second leading cause of long-term disability. In 2000, international groups including the World Health Organization launched an initiative to eliminate lymphatic filariasis by conducting mass drug administrations. Although the compounds available for this program (ivermectin, albendazole, diethylcarbamazine) are effective at killing larvae (microfilariae), the adult reservoir of parasites (macrofilariae) survive and can remain in the body for a decade. In addition, the extreme selective pressure of mass treatment has lead to recent signs of parasite drug resistance. Similar challenges face the campaigns to reduce onchocerciasis with ivermectin. The long-term objective of this project is to develop new compounds with 'macrofilaricidal' activity that are desperately needed to complement the current regimens. During Phase I efforts, bioinformatic filters and functional genomic (RNAi) data from the model nematode Caenorhabitis elegans and the filarial parasite Brugia malayi were utilized to successfully identify and prioritize a small set of molecular targets predicted to be critical for macrofilarial survival. In addition, as a prelude to Phase II research, compounds previously demonstrated to possess nematicidal activity at Divergence were tested against Brugia spp. in vitro, with some compounds showing promising macrofilaricidal effects. In the current research, two well-characterized and essential enzymes from a filarial nematode biosynthetic pathway will be expressed and inhibitors identified through a combination of high-throughput chemical library screening and targeted cheminformatic approaches. The best hits will be evaluated against adult B. malayi and in vitro and assayed for mammalian cytotoxicity and microsomal stability. Finally, the most promising compounds will progress into rodent model trials of lymphatic filariasis. The expected outcome of this work is the identification of lead molecules that demonstrate macrofilaricidal activity within animal models. In collaboration with agencies that have demonstrated a commitment to global health equity (such as the Gates Foundation or WHO), Phase III efforts will focus on the initiation of clinical trials in humans--with the ultimate goal of eliminating the human health burden of filarial diseases. (Relevance to public health) Parasitic nematodes (roundworms) currently infect over 1 billion people globally, causing severe morbidity and considerable economic losses. This project is structured to identify desperately needed drugs to combat filarial nematodes, which constitute the most significant of the human tropical cluster diseases. Filarial parasites cause some of the more pernicious nematode-borne diseases known (elephantiasis and river blindness).