Chronic filarial infections remain a global health burden, with limited adulticidal therapies highlighting the need for new drugs. We explored repurposing human GPCR antagonists, including clemizole, pimozide, proroxan, and suloctidil, along with 45 rationally designed analogs for activity against Brugia pahangi and two Onchocerca species. Of those, 27 showed in vitro adulticidal activity. In vivo, clemizole and analog C-8 significantly reduced worm burden by 60.5% and 50.8%, respectively, while S-17 and PMZ-6 modestly reduced worm burden (36% and 25%, respectively); however, all three significantly reduced worm fecundity. C-8 also downregulated GPCR expression in surviving adult females after in vivo treatment. Radioligand binding assays revealed selective human GPCR affinities, with clemizole and suloctidil analogs having increased parasite selectivity. Caenorhabditis elegans reverse genetics screen identified gar-3 and ser-7 as putative nematode targets of clemizole and its analogs. Clemizole, C-8, and S-17 represent promising leads for further optimization as antifilarial drugs.
Rosa et al. (Sat,) studied this question.