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Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides

The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs....

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Autores principales: Bajraktari-Sylejmani, Gzona, von Linde, Teresa, Burhenne, Jürgen, Haefeli, Walter Emil, Sauter, Max, Weiss, Johanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415731/
https://www.ncbi.nlm.nih.gov/pubmed/36015235
http://dx.doi.org/10.3390/pharmaceutics14081610
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author Bajraktari-Sylejmani, Gzona
von Linde, Teresa
Burhenne, Jürgen
Haefeli, Walter Emil
Sauter, Max
Weiss, Johanna
author_facet Bajraktari-Sylejmani, Gzona
von Linde, Teresa
Burhenne, Jürgen
Haefeli, Walter Emil
Sauter, Max
Weiss, Johanna
author_sort Bajraktari-Sylejmani, Gzona
collection PubMed
description The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs. We hypothesised that the cyclic drug peptides octreotide and pasireotide could be substrates of this transporter because their diameter can resemble the size of dipeptides or tripeptides due to their strong structural curvature and because they reach the systemic circulation in Beagle dogs. For investigating possible hPepT1 substrate characteristics, we generated and characterised a CHO-K1 cell line overexpressing SLC15A1 by transfection and selection via magnetic beads. Possible inhibition of the uptake of the prototypical substrate Gly-Sar by octreotide and pasireotide was screened, followed by quantifying the uptake of the cyclic peptides in cells overexpressing SLC15A1 compared with the parental cell line. Although inhibition of Gly-Sar uptake was observed, uptake of octreotide and pasireotide was not increased in SLC15A1 overexpressing cells, indicating a lack of transport by hPepT1. Our data clearly indicate that octreotide and pasireotide are nonsubstrate inhibitors of hPepT1 and that their oral bioavailability cannot be explained by absorption via hPepT1.
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spelling pubmed-94157312022-08-27 Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides Bajraktari-Sylejmani, Gzona von Linde, Teresa Burhenne, Jürgen Haefeli, Walter Emil Sauter, Max Weiss, Johanna Pharmaceutics Article The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs. We hypothesised that the cyclic drug peptides octreotide and pasireotide could be substrates of this transporter because their diameter can resemble the size of dipeptides or tripeptides due to their strong structural curvature and because they reach the systemic circulation in Beagle dogs. For investigating possible hPepT1 substrate characteristics, we generated and characterised a CHO-K1 cell line overexpressing SLC15A1 by transfection and selection via magnetic beads. Possible inhibition of the uptake of the prototypical substrate Gly-Sar by octreotide and pasireotide was screened, followed by quantifying the uptake of the cyclic peptides in cells overexpressing SLC15A1 compared with the parental cell line. Although inhibition of Gly-Sar uptake was observed, uptake of octreotide and pasireotide was not increased in SLC15A1 overexpressing cells, indicating a lack of transport by hPepT1. Our data clearly indicate that octreotide and pasireotide are nonsubstrate inhibitors of hPepT1 and that their oral bioavailability cannot be explained by absorption via hPepT1. MDPI 2022-08-01 /pmc/articles/PMC9415731/ /pubmed/36015235 http://dx.doi.org/10.3390/pharmaceutics14081610 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bajraktari-Sylejmani, Gzona
von Linde, Teresa
Burhenne, Jürgen
Haefeli, Walter Emil
Sauter, Max
Weiss, Johanna
Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title_full Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title_fullStr Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title_full_unstemmed Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title_short Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides
title_sort evaluation of pept1 (slc15a1) substrate characteristics of therapeutic cyclic peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415731/
https://www.ncbi.nlm.nih.gov/pubmed/36015235
http://dx.doi.org/10.3390/pharmaceutics14081610
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