title: Monepantel irreversibly binds to and opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 receptors.
abstract: Monepantel is a recently developed anthelmintic with a novel mode of action. Parasitic nematodes with reduced sensitivity to monepantel have led to the identification of MPTL-1, a ligand-gated ion-channel subunit of the parasitic nematode Haemonchus contortus, as a potential drug target. Homomeric MPTL-1 channels reconstituted in Xenopus oocytes are gated by µM concentrations of betaine and mM concentrations of choline. Measurement of reversal potentials indicated that the channel has a similar conductance for Na(+) and K(+) ions and does not permeate Ca(2+). Concentrations of monepantel (amino-acetonitrile derivative [AAD]-2225) >0.1 μM, but not its inactive enantiomer AAD-2224, induced channel opening in an irreversible manner. Currents elicited by monepantel alone were larger than the maximal current amplitudes achieved with betaine or choline, making monepantel a superagonist. Currents elicited by betaine or choline were allosterically potentiated by nM concentrations of monepantel and to a much smaller degree by AAD-2224. We have also reconstituted the Caenorhabditis elegans homomeric ACR-20 receptor in Xenopus oocytes. The acr-20 sequence has higher similarity to mptl-1 than acr-23, the primary target for monepantel mode of action in C. elegans. The ACR-20 channel is gated similarly as MPTL-1. Monepantel, but not AAD-2224, was able to induce channel opening in an irreversible manner at similar concentrations as for MPTL-1. Interestingly, the allosteric potentiation measured in the presence of betaine was much smaller than in MPTL-1 receptors. Together, these results establish the mode of action of monepantel in H. contortus and contribute to our understanding of the mode of action of this anthelmintic.
authors.affiliation: Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.).
authors.forename: Roland
authors.initials: R
authors.lastname: Baur
authors.affiliation: Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.).
authors.forename: Robin
authors.initials: R
authors.lastname: Beech
authors.affiliation: Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.).
authors.forename: Erwin
authors.initials: E
authors.lastname: Sigel
authors.affiliation: Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.) lucien.rufener@novartis.com.
authors.forename: Lucien
authors.initials: L
authors.lastname: Rufener
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001622:Betaine / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000378:metabolism; D002794:Choline / Q000494:pharmacology; D004357:Drug Synergism; D006189:Haemonchus / Q000378:metabolism; D015801:Helminth Proteins / Q000378:metabolism*; D058446:Ligand-Gated Ion Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics
chemical_list: D000871:Anthelmintics; D015801:Helminth Proteins; D058446:Ligand-Gated Ion Channels; D011978:Receptors, Nicotinic; D000607:Aminoacetonitrile; D001622:Betaine; C533978:monepantel; D002794:Choline