Abstract
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics—the benzimidazoles, imidazothiazoles and macrocyclic lactones—has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
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Acknowledgements
We thank F. Schroeder, E. Pradervand, S. Mulhauser, J. Lambert, D. Mosimann and A. Kazimi for technical assistance; C. Johnson for providing an ivermectin-resistant C. elegans strain; and C. Kempter for support on chemical characterization of AADs. We also thank S. Nanchen, B. Hosking, A. Redpath and R. Steiger for thorough review of and comments on the manuscript. P.M. is supported by the Swiss National Science Foundation.
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The file contains Supplementary Methods with details on the chemical synthesis of amino-acetonitrile derivatives (AADs); Supplementary Data with chiral resolution of AAD-1470 and biological activity of the enantiomers; Supplementary Figures S1-S2 illustrating NMR spectra of AADs (Figure S1) and multiple alignment of nicotinic acetylcholine receptor alpha-subunits (Figure S2); and Supplementary Tables S1-S3 with pharmacological (Tables S1 and S3) and genetic (Table S2) data of Caenorhabditis elegans mutants. (PDF 698 kb)
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Kaminsky, R., Ducray, P., Jung, M. et al. A new class of anthelmintics effective against drug-resistant nematodes. Nature 452, 176–180 (2008). https://doi.org/10.1038/nature06722
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DOI: https://doi.org/10.1038/nature06722
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