title: Recognition of 2-aminothiazole-4-acetic acid derivatives by the peptide transporters PEPT1 and PEPT2.
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.
authors.affiliation: Institute of Biochemistry and Biotechnology, Faculty of Sciences I, Martin-Luther-University Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Biegel
authors.forename: Sabine
authors.initials: S
authors.lastname: Gebauer
authors.forename: Bianka
authors.initials: B
authors.lastname: Hartrodt
authors.forename: Ilka
authors.initials: I
authors.lastname: Knütter
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandsch
authors.forename: Iris
authors.initials: I
authors.lastname: Thondorf
mesh_terms: 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
chemical_list: 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