In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1. / Andersen, Rikke; Nielsen, Carsten Uhd; Begtrup, Mikael; Jørgensen, Flemming Steen; Brodin, Birger; Frokjaer, Sven; Steffansen, Bente.

In: European Journal of Pharmaceutical Sciences, Vol. 28, No. 4, 2006, p. 325-35.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Andersen, R, Nielsen, CU, Begtrup, M, Jørgensen, FS, Brodin, B, Frokjaer, S & Steffansen, B 2006, 'In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1', European Journal of Pharmaceutical Sciences, vol. 28, no. 4, pp. 325-35. https://doi.org/10.1016/j.ejps.2006.03.007

APA

Andersen, R., Nielsen, C. U., Begtrup, M., Jørgensen, F. S., Brodin, B., Frokjaer, S., & Steffansen, B. (2006). In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1. European Journal of Pharmaceutical Sciences, 28(4), 325-35. https://doi.org/10.1016/j.ejps.2006.03.007

Vancouver

Andersen R, Nielsen CU, Begtrup M, Jørgensen FS, Brodin B, Frokjaer S et al. In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1. European Journal of Pharmaceutical Sciences. 2006;28(4):325-35. https://doi.org/10.1016/j.ejps.2006.03.007

Author

Andersen, Rikke ; Nielsen, Carsten Uhd ; Begtrup, Mikael ; Jørgensen, Flemming Steen ; Brodin, Birger ; Frokjaer, Sven ; Steffansen, Bente. / In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1. In: European Journal of Pharmaceutical Sciences. 2006 ; Vol. 28, No. 4. pp. 325-35.

Bibtex

@article{f644a89df85648089db01cbb633a717a,
title = "In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1",
abstract = "Oral absorption of tripeptides is generally mediated by the human intestinal di-/tri-peptide transporter, hPEPT1. However, the bioavailability of tripeptides is often limited due to degradation in the GI-tract by various peptidases. The aim of the present study was to evaluate the general application of N-methyl amide bioisosteres as peptide bond replacements in tripeptides in order to decrease degradation by peptidases and yet retain affinity for and transport via hPEPT1. Seven structurally diverse N-methyl amide tripeptidomimetics were selected based on a principal component analysis of structural properties of 6859 N-methyl amide tripeptidomimetics. In vitro extracellular degradation of the selected tripeptidomimetics as well as affinity for and transepithelial transport via hPEPT1 were investigated in Caco-2 cells. Decreased apparent degradation was observed for all tripeptidomimetics compared to the corresponding natural tripeptides. However, affinity for and transepithelial transport via hPEPT1 were only seen for Gly-Sar-Sar, AsnPsi[CONCH(3)]PhePsi[CONCH(3)]Trp, and Gly-Sar-Leu. This implies that tripeptidomimetics originating from tripeptides with neutral side chains are more likely to be substrates for hPEPT1 than tripeptidomimetics with charged side chains. The results of the present study indicate that the N-methyl amide peptide bond replacement approach for increasing bioavailability of tripeptidomimetic drug candidates is not generally applicable to all tripeptides. Nevertheless, retained affinity for and transport via hPEPT1 were shown for three of the evaluated N-methyl amide tripeptidomimetics.",
keywords = "Amides, Caco-2 Cells, Drug Design, Drug Stability, Humans, Intestinal Mucosa, Kinetics, Methylation, Molecular Structure, Oligopeptides, Peptide Hydrolases, Principal Component Analysis, Structure-Activity Relationship, Symporters",
author = "Rikke Andersen and Nielsen, {Carsten Uhd} and Mikael Begtrup and J{\o}rgensen, {Flemming Steen} and Birger Brodin and Sven Frokjaer and Bente Steffansen",
year = "2006",
doi = "10.1016/j.ejps.2006.03.007",
language = "English",
volume = "28",
pages = "325--35",
journal = "Norvegica Pharmaceutica Acta",
issn = "0928-0987",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - In vitro evaluation of N-methyl amide tripeptidomimetics as substrates for the human intestinal di-/tri-peptide transporter hPEPT1

AU - Andersen, Rikke

AU - Nielsen, Carsten Uhd

AU - Begtrup, Mikael

AU - Jørgensen, Flemming Steen

AU - Brodin, Birger

AU - Frokjaer, Sven

AU - Steffansen, Bente

PY - 2006

Y1 - 2006

N2 - Oral absorption of tripeptides is generally mediated by the human intestinal di-/tri-peptide transporter, hPEPT1. However, the bioavailability of tripeptides is often limited due to degradation in the GI-tract by various peptidases. The aim of the present study was to evaluate the general application of N-methyl amide bioisosteres as peptide bond replacements in tripeptides in order to decrease degradation by peptidases and yet retain affinity for and transport via hPEPT1. Seven structurally diverse N-methyl amide tripeptidomimetics were selected based on a principal component analysis of structural properties of 6859 N-methyl amide tripeptidomimetics. In vitro extracellular degradation of the selected tripeptidomimetics as well as affinity for and transepithelial transport via hPEPT1 were investigated in Caco-2 cells. Decreased apparent degradation was observed for all tripeptidomimetics compared to the corresponding natural tripeptides. However, affinity for and transepithelial transport via hPEPT1 were only seen for Gly-Sar-Sar, AsnPsi[CONCH(3)]PhePsi[CONCH(3)]Trp, and Gly-Sar-Leu. This implies that tripeptidomimetics originating from tripeptides with neutral side chains are more likely to be substrates for hPEPT1 than tripeptidomimetics with charged side chains. The results of the present study indicate that the N-methyl amide peptide bond replacement approach for increasing bioavailability of tripeptidomimetic drug candidates is not generally applicable to all tripeptides. Nevertheless, retained affinity for and transport via hPEPT1 were shown for three of the evaluated N-methyl amide tripeptidomimetics.

AB - Oral absorption of tripeptides is generally mediated by the human intestinal di-/tri-peptide transporter, hPEPT1. However, the bioavailability of tripeptides is often limited due to degradation in the GI-tract by various peptidases. The aim of the present study was to evaluate the general application of N-methyl amide bioisosteres as peptide bond replacements in tripeptides in order to decrease degradation by peptidases and yet retain affinity for and transport via hPEPT1. Seven structurally diverse N-methyl amide tripeptidomimetics were selected based on a principal component analysis of structural properties of 6859 N-methyl amide tripeptidomimetics. In vitro extracellular degradation of the selected tripeptidomimetics as well as affinity for and transepithelial transport via hPEPT1 were investigated in Caco-2 cells. Decreased apparent degradation was observed for all tripeptidomimetics compared to the corresponding natural tripeptides. However, affinity for and transepithelial transport via hPEPT1 were only seen for Gly-Sar-Sar, AsnPsi[CONCH(3)]PhePsi[CONCH(3)]Trp, and Gly-Sar-Leu. This implies that tripeptidomimetics originating from tripeptides with neutral side chains are more likely to be substrates for hPEPT1 than tripeptidomimetics with charged side chains. The results of the present study indicate that the N-methyl amide peptide bond replacement approach for increasing bioavailability of tripeptidomimetic drug candidates is not generally applicable to all tripeptides. Nevertheless, retained affinity for and transport via hPEPT1 were shown for three of the evaluated N-methyl amide tripeptidomimetics.

KW - Amides

KW - Caco-2 Cells

KW - Drug Design

KW - Drug Stability

KW - Humans

KW - Intestinal Mucosa

KW - Kinetics

KW - Methylation

KW - Molecular Structure

KW - Oligopeptides

KW - Peptide Hydrolases

KW - Principal Component Analysis

KW - Structure-Activity Relationship

KW - Symporters

U2 - 10.1016/j.ejps.2006.03.007

DO - 10.1016/j.ejps.2006.03.007

M3 - Journal article

C2 - 16713701

VL - 28

SP - 325

EP - 335

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

IS - 4

ER -

ID: 38393549