Inhibitors for a conserved filarial catechol-O-methyltransferase with potent efficacy against all life-stages of Brugia malayi infection in gerbils

Filarial nematodes of genus Brugia cause lymphatic filariasis, with over 36 million chronically debilitated people and 885 million at risk in Asia and sub-Saharan Africa. Current drugs have limited efficacy. Herein, we unveil a unique catechol-O-methyltransferase (COMT) called BmMT that is conserved in filarial nematodes with a lethal RNAi phenotype in Caenorhabditis elegans and lacks orthologs in mammals. COMTs catabolize catecholamines that if left to accumulate are lethal in nematodes. BmMT possesses core structural and functional features of COMTs, but is divergent from mammalian COMTs. Three inhibitors of BmMT (NSC177383, NSC133100, and NSC56410) depicted potent activity against all life-stages of B. malayi. The inhibitors bind within BmMT’s catechol substrate-binding fold with high occupancy (> 80%) of residues, implying they block catecholamine binding. As proof of principle for the mode of action of BmMT inhibitors, treatment of B. malayi worms with NSC56410 elevated catecholamines, consistent with observations using morpholino-mediated knockdown of BmMT. Importantly, treatment of B. malayi-infected gerbils with NSC133100 (100 mg/kg/day) or NSC56410 (10 mg/kg/day) almost completely eliminated all microfilariae and adult worms. Together, these studies unveil BmMT as a promising new molecular target, with its selective inhibitors as optimizable lead-compounds for the development of novel efficacious antifilarial drugs.