Polymorphism in ion channel genes of Dirofilaria immitis: Relevant knowledge for future anthelmintic drug design
| Autor: | Kathy Keller, Roger K. Prichard, Catherine Bourguinat, Andrew S. Peregrine, Elena Carretón, Thangadurai Mani |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug targets Protein Conformation Dirofilaria immitis 030231 tropical medicine Loss of efficacy Single-nucleotide polymorphism Polymorphism Single Nucleotide Genome Ion Channels lcsh:Infectious and parasitic diseases 03 medical and health sciences Exon 0302 clinical medicine Neuromuscular system Animals lcsh:RC109-216 Pharmacology (medical) Genetic variability Gene Anthelmintics Pharmacology Whole genome sequencing Genetics Macrocyclic lactones biology biology.organism_classification Phenotype Single nucleotide polymorphism 3. Good health 030104 developmental biology Infectious Diseases Invited Article Drug Design Parasitology |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance International Journal for Parasitology: Drugs and Drug Resistance, Vol 6, Iss 3, Pp 343-355 (2016) |
| ISSN: | 2211-3207 |
| DOI: | 10.1016/j.ijpddr.2016.06.003 |
| Popis: | Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite. Any new drug that targets these ion channels is likely to have a motility phenotype and should act to clear the worms from the host. Many of the successful anthelmintics in the past have targeted these ion channels and receptors. Knowledge about genetic variability of the ion channel and receptor genes should be useful information for drug design as receptor polymorphism may affect responses to a drug. Such information may also be useful for anticipation of possible resistance development. A total of 224 ion channel genes/subunits have been identified in the genome of D. immitis. Whole genome sequencing data of parasites from eight different geographical locations, four from ML-susceptible populations and the other four from ML-loss of efficacy (LOE) populations, were used for polymorphism analysis. We identified 1762 single nucleotide polymorphic (SNP) sites (1508 intronic and 126 exonic) in these 224 ion channel genes/subunits with an overall polymorphic rate of 0.18%. Of the SNPs found in the exon regions, 129 of them caused a non-synonymous type of polymorphism. Fourteen of the exonic SNPs caused a change in predicted secondary structure. A few of the SNPs identified may have an effect on gene expression, function of the protein and resistance selection processes. Graphical abstract Highlights • In the Dirofilaria immitis genome, 126 ion channel genes were identified. • Within 126 ion channel genes, 1762 polymorphic loci were identified. • Fourteen exonic SNPs caused a change in predicted secondary structure. • SNPs may effect gene expression, protein function or resistance selection. • D. immitis populations have low genetic variability among ion channel genes. |
| Databáze: | OpenAIRE |
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