Recognition of 2-aminothiazole-4-acetic acid derivatives by the peptide transporters PEPT1 and PEPT2

Annegret Biegel; Sabine Gebauer; Bianka Hartrodt; Ilka Knütter; Klaus Neubert; Matthias Brandsch; Iris Thondorf

doi:10.1016/j.ejps.2007.06.002

Recognition of 2-aminothiazole-4-acetic acid derivatives by the peptide transporters PEPT1 and PEPT2

Eur J Pharm Sci. 2007 Sep;32(1):69-76. doi: 10.1016/j.ejps.2007.06.002. Epub 2007 Jun 13.

Authors

Annegret Biegel¹, Sabine Gebauer, Bianka Hartrodt, Ilka Knütter, Klaus Neubert, Matthias Brandsch, Iris Thondorf

Affiliation

¹ Institute of Biochemistry and Biotechnology, Faculty of Sciences I, Martin-Luther-University Halle-Wittenberg, D-06120 Halle, Germany.

PMID: 17644326
DOI: 10.1016/j.ejps.2007.06.002

Abstract

The H(+)/peptide cotransporters PEPT1 and PEPT2 have gained considerable interest in pharmaceutical sciences as routes for drug delivery. It is, therefore, of interest to develop uncommon artificial substrates for the two carriers. This study was initiated to investigate the binding affinity of 2-aminothiazole-4-acetic acid (ATAA) conjugates with amino acids to PEPT1 and PEPT2. The 2-aminothiazole-4-acetic acid derivatives have been synthesised and tested for their affinity to PEPT1 and PEPT2. The K(i) values were compared with in silico predicted values from CoMSIA models. C-terminal ATAA-Xaa conjugates proved to be low to medium inhibitors of the [(14)C]Gly-Sar uptake at both carrier systems whereas N-terminal Xaa-ATAA conjugates exhibited medium to high affinity. A promising candidate for further functionalisation is Val-ATAA which shows extraordinary high affinity to PEPT1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / chemistry
Amino Acids / metabolism
Amino Acids / pharmacokinetics
Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacokinetics
Biological Transport / drug effects
Biological Transport / physiology
Caco-2 Cells
Ceftibuten
Cells, Cultured
Cephalosporins / chemistry
Cephalosporins / metabolism*
Cephalosporins / pharmacokinetics
Dipeptides / chemistry
Dipeptides / metabolism
Dipeptides / pharmacokinetics
Humans
Kidney Tubules, Proximal / cytology
Kidney Tubules, Proximal / metabolism
Kinetics
Models, Molecular
Molecular Structure
Oligopeptides / chemistry
Oligopeptides / metabolism
Oligopeptides / pharmacokinetics
Peptide Transporter 1
Protein Binding
Rats
Symporters / antagonists & inhibitors
Symporters / metabolism*
Symporters / physiology

Substances

Amino Acids
Anti-Bacterial Agents
Cephalosporins
Dipeptides
Oligopeptides
Peptide Transporter 1
Symporters
hydrogen-coupled oligopeptide transporter PepT2
alanylalanine
glycylsarcosine
alanyl-alanyl-alanine
Ceftibuten