Phylogenomics of ligand-gated ion channels predicts monepantel effect

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 (ec50<1.25 μm),whereas the related nematodes pristionchus pacificus and strongyloides ratti,which lack an acr-23/ mptl-1 homolog,are insensitive (ec50>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. © 2010 rufener et al.