Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus

Rufener, L. and Baur, R. and Kaminsky, R. and Mäser, P. and Sigel, E.. (2010) Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus. Molecular pharmacology : an international journal, Vol. 78, H. 5. pp. 895-902.

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Official URL: http://edoc.unibas.ch/dok/A5842954

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Monepantel is the first drug of a new family of anthelmintics, the amino acetonitrile derivatives (AAD), presently used to treat ruminants infected with gastrointestinal nematodes such as Haemonchus contortus. Monepantel shows an excellent tolerability in mammals and is active against multidrug-resistant parasites, indicating that its molecular target is (i) absent or inaccessible in the host and (ii) different from those of the classical anthelmintics. Genetic approaches with mutant nematodes have suggested acetylcholine receptors of the DEG-3 subfamily as the targets of AADs, an enigmatic clade of ligand-gated ion channels that is specific to nematodes and does not occur in mammals. Here we demonstrate direct interaction of monepantel, its major active metabolite monepantel sulfone, and other AADs with potential targets of the DEG-3 subfamily of acetylcholine receptors. Haemonchus contortus DEG-3/DES-2 receptors were functionally expressed in Xenopus oocytes and found to be preferentially activated by choline, to permeate monovalent cations, and to a smaller extent, calcium ions. While monepantel and monepantel sulfone did not activate the channels by themselves, they substantially enhanced the late currents after activation of the channels with choline, indicating that these AADs are type II positive allosteric modulators of H. contortus DEG-3/DES-2 channels. Interestingly, the inactive, R enantiomer of monepantel inhibited the late currents after stimulation of H. contortus DEG-3/DES-2 receptors with choline. In summary, we present the first direct evidence for interaction of AADs with DEG-3 type acetylcholine receptors and discuss these findings in the context of anthelmintic action of AADs
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Academic Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:19
Deposited On:14 Sep 2012 06:48

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