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

Sean Harrington, Jacob Pyche, Andrew R. Burns, Tina Spalholz, Kaetlyn T. Ryan, Rachel J. Baker, Justin Ching, Lucien Rufener, Mark Lautens, Daniel Kulke, Alexandre Vernudachi, Mostafa Zamanian, Winnie Deuther-Conrad, Peter Brust and Peter J. Roy ()
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Sean Harrington: University of Toronto
Jacob Pyche: University of Toronto
Andrew R. Burns: University of Toronto
Tina Spalholz: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf
Kaetlyn T. Ryan: University of Wisconsin-Madison
Rachel J. Baker: University of Toronto
Justin Ching: University of Toronto
Lucien Rufener: INVENesis Sàrl, Route de Neuchâtel 15A
Mark Lautens: University of Toronto
Daniel Kulke: Research Parasiticides, Bayer Animal Health GmbH
Alexandre Vernudachi: INVENesis France Sàrl
Mostafa Zamanian: University of Wisconsin-Madison
Winnie Deuther-Conrad: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf
Peter Brust: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf
Peter J. Roy: University of Toronto

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37452-6

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