title: Phylogenomics of ligand-gated ion channels predicts monepantel effect.
abstract: The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL-1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC(50)<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC(50)>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.
authors.affiliation: Novartis Centre de Recherche Santé Animale, St. Aubin, Switzerland.
authors.forename: Lucien
authors.initials: L
authors.lastname: Rufener
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.forename: Ronald
authors.initials: R
authors.lastname: Kaminsky
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D000969:Antinematodal Agents / Q000494:pharmacology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D049751:Genome, Helminth; D006188:Haemonchiasis / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology; D006189:Haemonchus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D058446:Ligand-Gated Ion Channels / Q000235:genetics* / Q000378:metabolism; D009348:Nematoda / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D009349:Nematode Infections / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology; D010270:Parasite Egg Count; D010802:Phylogeny; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology; D016896:Treatment Outcome
chemical_list: C528080:ACR-23 protein, C elegans; D000871:Anthelmintics; D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D058446:Ligand-Gated Ion Channels; D011978:Receptors, Nicotinic; D000607:Aminoacetonitrile; C533978:monepantel