Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect

PLoS Pathogens

Jennifer Keiser¹  Lucien Rufener²  Daniel Nilsson²  Ronald Kaminsky³  Pascal Mäser⁴ 

[1] Institute of Cell Biology, University of Bern, Bern, Switzerland;Novartis Centre de Recherche Santé Animale, St. Aubin, Switzerland;Swiss Tropical and Public Health Institute, Basel, Switzerland;University of Basel, Basel, Switzerland

关键词: Caenorhabditis elegans;    Sequence motif analysis;    Invertebrate genomics;    Nematoda;    Polymerase chain reaction;    Vertebrata;    Lig;    -gated ion channels;    Nicotinic acetylcholine receptors;   

DOI  :  10.1371/journal.ppat.1001091

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY