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Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile
P-glycoproteins from the ATP-binding cassette transporter family are responsible for drug evasion by bacterial pathogens and neoplastic cells. More recently, these multidrug resistance transporters have been investigated for contributions to drug resistance in nematode parasites. In this study, we c...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586496/ https://www.ncbi.nlm.nih.gov/pubmed/34753107 http://dx.doi.org/10.1016/j.ijpddr.2021.10.002 |
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author | Jesudoss Chelladurai, Jeba R.J. Jones, Douglas E. Brewer, Matthew T. |
author_facet | Jesudoss Chelladurai, Jeba R.J. Jones, Douglas E. Brewer, Matthew T. |
author_sort | Jesudoss Chelladurai, Jeba R.J. |
collection | PubMed |
description | P-glycoproteins from the ATP-binding cassette transporter family are responsible for drug evasion by bacterial pathogens and neoplastic cells. More recently, these multidrug resistance transporters have been investigated for contributions to drug resistance in nematode parasites. In this study, we cloned and characterized the P-glycoprotein Tca-Pgp-11.1 from Toxocara canis, the canine intestinal ascarid. Large numbers of Tca-Pgp-11 transcripts were observed in the intestine of adult male and female worms. Heterologous expression studies confirmed sensitivity to known P-glycoprotein inhibitors. Interestingly, the competitive inhibitor verapamil had lower IC(50) values than newer generation inhibitors that are designed to allosterically modulate mammalian P-glycoprotein. Consistent with other nematode P-glycoproteins, Tca-Pgp-11.1 was sensitive to ivermectin and selamectin but not moxidectin. Taken together, our data suggests that T. canis P-glycoproteins represent nematode-specific drug targets that could be exploited to enhance efficacy of existing anthelmintics. |
format | Online Article Text |
id | pubmed-8586496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-85864962021-11-19 Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile Jesudoss Chelladurai, Jeba R.J. Jones, Douglas E. Brewer, Matthew T. Int J Parasitol Drugs Drug Resist Regular article P-glycoproteins from the ATP-binding cassette transporter family are responsible for drug evasion by bacterial pathogens and neoplastic cells. More recently, these multidrug resistance transporters have been investigated for contributions to drug resistance in nematode parasites. In this study, we cloned and characterized the P-glycoprotein Tca-Pgp-11.1 from Toxocara canis, the canine intestinal ascarid. Large numbers of Tca-Pgp-11 transcripts were observed in the intestine of adult male and female worms. Heterologous expression studies confirmed sensitivity to known P-glycoprotein inhibitors. Interestingly, the competitive inhibitor verapamil had lower IC(50) values than newer generation inhibitors that are designed to allosterically modulate mammalian P-glycoprotein. Consistent with other nematode P-glycoproteins, Tca-Pgp-11.1 was sensitive to ivermectin and selamectin but not moxidectin. Taken together, our data suggests that T. canis P-glycoproteins represent nematode-specific drug targets that could be exploited to enhance efficacy of existing anthelmintics. Elsevier 2021-10-23 /pmc/articles/PMC8586496/ /pubmed/34753107 http://dx.doi.org/10.1016/j.ijpddr.2021.10.002 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Regular article Jesudoss Chelladurai, Jeba R.J. Jones, Douglas E. Brewer, Matthew T. Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title | Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title_full | Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title_fullStr | Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title_full_unstemmed | Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title_short | Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile |
title_sort | characterization of a p-glycoprotein drug transporter from toxocara canis with a novel pharmacological profile |
topic | Regular article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586496/ https://www.ncbi.nlm.nih.gov/pubmed/34753107 http://dx.doi.org/10.1016/j.ijpddr.2021.10.002 |
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