Recognition of 2-aminothiazole-4-acetic acid derivatives by the peptide transporters PEPT1 and PEPT2.
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.
Biegel
Annegret
A
Institute of Biochemistry and Biotechnology, Faculty of Sciences I, Martin-Luther-University Halle-Wittenberg, D-06120 Halle, Germany.
Gebauer
Sabine
S
Hartrodt
Bianka
B
Knütter
Ilka
I
Neubert
Klaus
K
Brandsch
Matthias
M
Thondorf
Iris
I
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D000077722:Ceftibuten; D002478:Cells, Cultured; D002511:Cephalosporins / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000074011:Peptide Transporter 1; D011485:Protein Binding; D051381:Rats; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004151:Dipeptides; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C002956:alanylalanine; C004194:glycylsarcosine; C039944:alanyl-alanyl-alanine; D000077722:Ceftibuten