1.Affinity and translocation relationships via hPEPT1 of H-X aa-Ser-OH dipeptides: evaluation of H-Phe-Ser-OH as a pro-moiety for ibuprofen and benzoic acid prodrugs.
Omkvist DH1, Trangbæk DJ, Mildon J, Paine JS, Brodin B, Begtrup M, Nielsen CU. Eur J Pharm Biopharm. 2011 Feb;77(2):327-31. doi: 10.1016/j.ejpb.2010.12.009. Epub 2010 Dec 13.
The intestinal di/tri-peptide transporter 1 (hPEPT1) has been suggested as a drug delivery target for peptide-based prodrugs. The aim of the study was to synthesize a series of 11 serine-containing dipeptides (H-X(aa)-Ser-OH) and to investigate the relationship between binding to and transport via hPEPT1. An additional aim was to design a dipeptide which could serve as a pro-moiety for prodrugs targeted to hPEPT1. X(aa) was chosen from the 20 proteogenic amino acids. The dipeptides were synthesized using solid phase peptide synthesis. The K(i)-values of H-X(aa)-Ser-OH dipeptides for hPEPT1 in MDCK/hPEPT1 cells ranged from 0.14 mM (logIC(50)=-0.85 ± 0.06) for H-Tyr-Ser-OH to 0.89 mM (logIC(50)=-0.09 ± 0.02) for H-Gly-Ser-OH, as measured in a competition assay with [(14)C]Gly-Sar. The dipeptides were translocated via hPEPT1 with K(m)-values in the range of 0.20 (logIC(50)=-0.69 ± 0.04) for H-Met-Ser-OH to 1.04 (logIC(50)=0.02 ± 0.04) mM for H-Gly-Ser-OH.
