Human PEPT1 Pharmacophore Distinguishes between Dipeptide Transport and Binding

Vig, Balvinder S.; Stouch, Terry R.; Timoszyk, Julita; Quan, Yong; Wall, Doris A.; Smith, Ronald L.; Faria, Teresa N.

doi:10.1021/jm0511029

Cited by 112 publications

(103 citation statements)

References 39 publications

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“…The translocation was drastically reduced or completely abolished when Trp was positioned in the middle of the tripeptide (Gly-Trp-Val and Pro-Trp-Ile). In a study by Vig et al, it was noted that Trp in the C-terminal position either resulted in a reduced or a complete lack of translocation of dipeptides (22), which is in agreement with our results.…”

Section: Estimation Of Substrate Translocation Via Hpept1supporting

confidence: 94%

“…We found that Trp-Trp-Trp was an inhibitor of hPEPT1 which is in agreement with a previous study (32). Previously, Lys-Arg, Lys-Lys, Lys-Trp, Pro-Arg, Pro-Asp, Pro-Glu, Pro-Gly, Pro-Lys, Pro-Phe, Pro-Ser, ProTyr, Trp-Tyr and Trp-Trp have also been identified as not being substrates for hPEPT1 (22,32). One could speculate that Lys-Arg and Lys-Lys, both having a net positive charge of +2, may have interacted with the assay system, as their method was similar to ours (22).…”

Section: Substrates and Inhibitors Of Hpept1supporting

confidence: 93%

“…Translocation properties of a large number of dipeptides had already been tested by Vig et al (22). Therefore, it was decided to base the compound selection on tripeptides in the present study.…”

Section: Computational Proceduresmentioning

confidence: 99%

“…Several inhibitors of hPEPT1 have been identified including L-Glu(trans-2-thymidine-1-yltetrahydrofuran-3-yl ester)-Sar, L-Glu(acyclothymidine)-Sar, Glu(acyclovir)-Sar, Lys[Z(NO2)]-Pro and 4-aminomethylbencoic acid (18)(19)(20)(21). The relationship between affinity and translocation via hPEPT1 of a large number of dipeptides has been reported, but no structure-translocation relationship by means of a QSAR model has been made (22).…”

Section: Introductionmentioning

confidence: 99%

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A Quantitative Structure–Activity Relationship for Translocation of Tripeptides via the Human Proton-Coupled Peptide Transporter, hPEPT1 (SLC15A1)

Omkvist

Larsen

Nielsen

et al. 2010

AAPS J

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Abstract. The human intestinal proton-coupled peptide transporter, hPEPT1 (SLC15A1), has been identified as an absorptive transporter for both drug substances and prodrugs. An understanding of the prerequisites for transport has so far been obtained from models based on competition experiments. These models have limited value for predicting substrate translocation via hPEPT1. The aim of the present study was to investigate the requirements for translocation via hPEPT1. A set of 55 tripeptides was selected from a principal component analysis based on VolSurf descriptors using a statistical design. The majority of theses tripeptides have not previously been investigated. Translocation of the tripeptides via hPEPT1 was determined in a MDCK/hPEPT1 cell-based translocation assay measuring substrateinduced changes in fluorescence of a membrane potential-sensitive probe. Affinities for hPEPT1 of relevant tripeptides were determined by competition studies with [14 C]Gly-Sar in MDCK/hPEPT1 cells. Forty tripeptides were found to be substrates for hPEPT1, having K m app values in the range 0.4-28 mM. Eight tripeptides were not able to cause a substrate-induced change in fluorescence in the translocation assay and seven tripeptides interacted with the probe itself. The conformationally restricted tripeptide Met-Pro-Pro was identified as a novel high-affinity inhibitor of hPEPT1. We also discovered the first tripeptide (Asp-Ile-Arg) that was neither a substrate nor an inhibitor of hPEPT1. To rationalise the requirements for transport, a quantitative structure-activity relationship model correlating K m app values with VolSurf descriptors was constructed. This is, to our knowledge, the first predictive model for the translocation of tripeptides via hPEPT1.

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Section: Estimation Of Substrate Translocation Via Hpept1supporting

confidence: 94%

Section: Substrates and Inhibitors Of Hpept1supporting

confidence: 93%

Section: Computational Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Quantitative Structure–Activity Relationship for Translocation of Tripeptides via the Human Proton-Coupled Peptide Transporter, hPEPT1 (SLC15A1)

Omkvist

Larsen

Nielsen

et al. 2010

AAPS J

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“…These di/tripeptides are removed from the nutrient rich intestinal lumen by a H + /peptide symporter, peptide transporter 1 or PepT1 (1). This transporter is localized to the apical surface of the intestinal villi and has broad substrate specificity.…”

mentioning

confidence: 99%

Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

Nosworthy

Brunton

2016

Pediatr Res

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Background: PepT1 transports dietary and bacterial peptides in the gut. We hypothesized that cysteinyl-glycine would ameliorate the inflammatory effect of a bacterial peptide, formylmethionyl-leucyl-phenylalanine (fMLP), in both sow-fed and parenterally-fed piglets. Methods: An intestinal perfusion experiment was performed in piglets (N = 12) that were sow-reared or provided with parenteral nutrition (PN) for 4 d. In each piglet, five segments of isolated intestine were perfused with five treatments including cysteine and glycine, cysteinyl-glycine, fMLP, free cysteine and glycine with fMLP, or cysteinyl-glycine with fMLP. Mucosal cytokine responses and intestinal morphology was assessed in each gut segment. results: PN piglets had lower mucosal IL-10 by approximately 20% (P < 0.01). Cysteinyl-glycine lowered TNF-α response to fMLP in PN-fed animals and IFN-γ response to fMLP in both groups (P < 0.05). The free cysteine and glycine treatment reduced TNF-α in sow-fed animals (P < 0.05). fMLP affected villus height in parenterally (P < 0.05), but not sow-fed animals. conclusion: Parenteral feeding conferred a susceptibility to mucosal damage by fMLP. The dipeptide was more effective at attenuating the inflammatory response to a bacterial peptide than free amino acids. This may be due to competitive inhibition of fMLP transport or a greater efficiency of transport of dipeptides. t he products of protein digestion that are absorbed by the small intestinal epithelium include free amino acids and small peptides of two to three residues in length. These di/tripeptides are removed from the nutrient rich intestinal lumen by a H + /peptide symporter, peptide transporter 1 or PepT1 (1). This transporter is localized to the apical surface of the intestinal villi and has broad substrate specificity. Potential substrates for PepT1 include almost all possible dietary di/ tripeptides (1), some antibiotics (2-4) and proinflammatory bacterial peptides (5-8).The primary neutrophil chemotactic substance produced by Escherichia coli is formyl-methionyl-leucyl-phenylalanine (fMLP) (9). This tripeptide is the most predominant N-formylated peptide present in the colonic lumen of humans (9).PepT1-mediated transport of fMLP has been demonstrated in cell culture where uptake of fMLP was inhibited by the presence of known substrates of PepT1 (10,11). Further, the presence of fMLP induced neutrophil migration across an epithelial monolayer, an activity that was abolished if fMLP uptake was inhibited. PepT1-mediated transport of fMLP has also been demonstrated using in vivo rat models (12,13). In particular, uptake of fMLP has been investigated in rats using an intestinal perfusion approach (12). Marked inflammatory response occurred in jejunal segments perfused with fMLP, an intestinal position known to have high expression of PepT1. This inflammation was accompanied by an increase in DNA binding by NFκβ, a transcription factor involved in the regulation of proinflammatory cytokines. This transcription factor is capable of inducing transcri...

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Transporter–Xenobiotic Interactions: An Important Aspect of Drug Development Studies

Luo

Ridgewell

Guenthner

2009

Enzyme Inhibition in Drug Discovery and Development

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Human PEPT1 Pharmacophore Distinguishes between Dipeptide Transport and Binding

Cited by 112 publications

References 39 publications

A Quantitative Structure–Activity Relationship for Translocation of Tripeptides via the Human Proton-Coupled Peptide Transporter, hPEPT1 (SLC15A1)

A Quantitative Structure–Activity Relationship for Translocation of Tripeptides via the Human Proton-Coupled Peptide Transporter, hPEPT1 (SLC15A1)

Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

Transporter–Xenobiotic Interactions: An Important Aspect of Drug Development Studies

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