Novel Macrofilaricidal Compounds: Target Identification and Chemical Optimizatio

DESCRIPTION (provided by applicant): Parasitic infect over 140 million people, with up to one billion at risk in 80 countries. Lymphatic filariasis creates an enormous health and economic burden within affected areas and is the second leading cause of long -term disability. In 2000, international groups including the World Health Organization (WHO) launched an initiative to eliminate lymphatic filariasis by annual mass drug administration. Although the compounds available for this ambitious program (ivermect in, albendazole, diethylcarbamazine) are effective at killing larvae (microfilariae), the adult reservoir of parasites (macrofilariae) survive and can remain in the human host for a decade. In addition, the extreme selective pressure caused by mass treatme nt has been accompanied by recent evidence of parasite drug resistance. Similar challenges face the campaigns to reduce onchocerciasis with ivermectin. The long- term objective of this SBIR proposal is to develop desperately needed macrofilaricidal compoun ds that can eliminate the adult parasite reservoir and protect current drugs from the development of broad resistance. Divergence has recently implemented a proprietary technology that represents a fundamental advance in molecular modeling and allo ws the identification of structurally unrelated compounds that have a shared mode of action. Divergence has already succeeded with this approach in creating a valuable chemical collection with a high rate (~17%) of potent hits against animal and plant para sitic nematodes. A number of compounds in the collection also have very promising macrofilaricidal activity against female and male Brugia malayi filarial worms in vitro. Two objectives will be accomplished during Phase I. First, as our compounds represent a broad and novel nematicidal mode of action, Divergence will initiate genetic studies in C. elegans to identify the compounds' molecular target. Second, structure-activity and optimization strategies will be pursued through the acquisition and synthesis of analogs. The resultant molecules will be evaluated against adult B. malayi in vitro and subsequently assayed for cytotoxicity in a mammalian cell line and microsomal stability. During Phase II studies, promising molecules will progress to evaluation of filarial control in a rodent model along with toxicology and pharmacokinetic evaluation. Molecular targets identified in the Phase I genetic screen will be cloned and characterized for use in development of next generation leads and eventual resistance mon itoring in a project compound reaching clinical use. The expected outcome of this work is the identification of potent lead molecules that demonstrate in vivo macrofilaricidal activity with a novel mode of action. In collaboration with agencies that have d emonstrated a commitment to global health equity (such as the Gates Foundation and WHO), Phase III efforts will focus on the initiation of clinical trials in humans with the ultimate goal of greatly reducing the human health burden of filarial diseases. Project Narrative: Parasitic nematodes (roundworms) currently infect over one billion people globally, causing severe morbidity and economic burden. The goal of this project to identify and develop desperately needed drugs to combat filarial nematodes , which cause some of the most pernicious infectious diseases in humans - elephantiasis and river blindness.