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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. Rece...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936538/ https://www.ncbi.nlm.nih.gov/pubmed/20838602 http://dx.doi.org/10.1371/journal.ppat.1001091 |
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author | Rufener, Lucien Keiser, Jennifer Kaminsky, Ronald Mäser, Pascal Nilsson, Daniel |
author_facet | Rufener, Lucien Keiser, Jennifer Kaminsky, Ronald Mäser, Pascal Nilsson, Daniel |
author_sort | Rufener, Lucien |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2936538 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29365382010-09-13 Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect Rufener, Lucien Keiser, Jennifer Kaminsky, Ronald Mäser, Pascal Nilsson, Daniel PLoS Pathog Research Article 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. Public Library of Science 2010-09-09 /pmc/articles/PMC2936538/ /pubmed/20838602 http://dx.doi.org/10.1371/journal.ppat.1001091 Text en Rufener et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rufener, Lucien Keiser, Jennifer Kaminsky, Ronald Mäser, Pascal Nilsson, Daniel Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title | Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title_full | Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title_fullStr | Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title_full_unstemmed | Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title_short | Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect |
title_sort | phylogenomics of ligand-gated ion channels predicts monepantel effect |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936538/ https://www.ncbi.nlm.nih.gov/pubmed/20838602 http://dx.doi.org/10.1371/journal.ppat.1001091 |
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