PLoS Pathogens | |
Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect | |
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
【 预 览 】
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