Compounds Targeting Nematode Secretion as Novel Anti-filarial Drugs

DESCRIPTION (provided by applicant): Worldwide, over 1 billion people suffer from debilitating diseases caused by parasitic nematode infections. Parasitic nematodes utilize secretory products to modulate the host immune system in order to establish and maintain the infection. Cambia Biosciences is developing novel chemical inhibitors of nematode secretion to treat parasitic infections like lymphatic filariasis and onchocerciasis. Using the model nematode Caenorhabditis elegans, we have identified 30 compounds that inhibited secretion from a collection of 10,000 small molecules screened. The goal of this Phase I project is to identify and partially characterize at least one compound from our 30 candidate molecules that disrupt secretion by the parasitic nematode Brugia malayi, a species representative of filarial parasites, which at the adult stage are refractory to existing antiparasitic drugs. Our Phase I aims are: 1) Identify one or more compounds that inhibit secretion from Brugia malayi adult parasitic nematodes in an in vitro assay. Up to eight compounds, deemed validated adult parasitic nematode secretion inhibitors, will be selected for analog studies in Specific Aim 2. 2) Conduct preliminary structure-activity relationship studies with analogs of the validated parasitic nematode secretion inhibitor compounds and select candidates for use in Phase II. We have identified pre-existing compounds that are structurally related to our panel of C. elegans secretion inhibitors. For each of the compounds selected in Specific Aim 1, we will obtain a series of analogs and rank order them by potency in the B. malayi in vitro secretion assay, in order to select candidate leads for Phase II and provide preliminary structure-activity relationship information to accelerate hit to lead conversion during Phase II. Feasibility of this approach will be demonstrated if at least one compound is identified that inhibits secretion by B. malayi adult parasitic nematodes. Compounds selected for Phase II studies will be evaluated for efficacy in an animal model of human parasitic nematode infection and optimized though medicinal chemistry, with the long-term goal of developing a novel antiparasitic drug to address this global public health need.