Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential

Abstract

Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.

Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans

“… Geary and Thompson, 2001 ) and, hence, UMW-9729 achieves anthelmintic activity via divergent pathways. Although these results may question the use of C. elegans as a surrogate model for antiparasitic discovery, it is clear, through the development of monepantel ( Kaminsky et al, 2008 ) and the anthelmintic candidate Nemacol ( Harrington et al, 2023 ), that C. elegans remains a useful system, with the caveat that drug testing also needs to be undertaken against one or more pertinent parasitic nematodes, including H. contortus .…”

Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans

“…Antagonism was defined by ZIP synergy values less than -10 and synergy was defined by ZIP synergy values greater than 10. This framework has recently been used to assess anthelmintic drug interactions in other nematode species [ 50 , 51 ].…”