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- Title
Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential.
- Authors
Harrington, Sean; Pyche, Jacob; Burns, Andrew R.; Spalholz, Tina; Ryan, Kaetlyn T.; Baker, Rachel J.; Ching, Justin; Rufener, Lucien; Lautens, Mark; Kulke, Daniel; Vernudachi, Alexandre; Zamanian, Mostafa; Deuther-Conrad, Winnie; Brust, Peter; Roy, Peter J.
- 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. Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.
- Subjects
CAENORHABDITIS elegans; SMALL molecules; ACETYLCHOLINE; IVERMECTIN; LIVESTOCK parasites; HAEMONCHUS contortus
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37452-6