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

Year: 2026

Type: article

Abstract: 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 absence of orthologs in mammals. COMTs catabolize catecholamines that if left to accumulate are lethal in nematodes. BmMT possesses core structural functional features of COMTs, but is divergent from mammalian COMTs. Three compounds (NSC17783, NSC133100, and NSC56410) with inhibitory activity against BmMT showed 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, indicating they target blocking catecholamine binding. As proof of principle for mode of action of BmMT inhibitors, treatment of B. malayi worms with NSC56410 elevated catecholamines, consistent with observations using morpholino-mediated knockdown of BmMT in B. malayi . Importantly, infection-and-treatment of gerbils showed that 4 days treatment with NSC133100 (100 mg/kg/day) or NSC56410 (10 mg/kg/day) eliminated both microfilariae and adult worms. Together, our studies unveil and validate a molecular target and its optimizable selective inhibitors for development of novel efficacious anti-filarial drugs.

Source: Scientific Reports

DOI: 10.1038/s41598-026-77258-2