Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Jesudoss Chelladurai, Jeba R.J., Jones, Douglas E., Brewer, Matthew T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
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
_version_ 1784597896094547968
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
work_keys_str_mv AT jesudosschelladuraijebarj characterizationofapglycoproteindrugtransporterfromtoxocaracaniswithanovelpharmacologicalprofile
AT jonesdouglase characterizationofapglycoproteindrugtransporterfromtoxocaracaniswithanovelpharmacologicalprofile
AT brewermatthewt characterizationofapglycoproteindrugtransporterfromtoxocaracaniswithanovelpharmacologicalprofile