Gene name: Solute carrier family 15 member 2 (SLC15A2)
The human peptide transporter 2, PEPT2, is a low-capacity/high-affinity proton-coupled cotransporter of diverse di- and tripeptides as well as peptidomimetic substrates, and is expressed in a variety of tissues, particularly in the kidney and brain. PEPT2 is primarily involved in the renal reabsorption of di-/tripeptides and drugs with peptide-like structures. In the kidney, PEPT2 function is complemented by PEPT1, a closely related, high-capacity/low-affinity transporter with predominant expression in small intestine. The efficient reabsorption of peptide-bound amino nitrogen at the apical membrane of renal proximal tubular epithelium is an important process in systemic nitrogen homeostasis . As DDIs are not reported or anticipated, there are no recommendations for PEPT2 transporter investigation in either the FDA or EMA guidance.
Highest expression of PEPT2 was detected in renal proximal tubular cells of the S2 and S3 segments. PEPT2 was also detected in brain astrocytes, mammary gland and bronchial epithelial cells, type II pneumocytes, and epithelial cells of the choroid plexus [1-4].
Function, physiology, and clinically significant polymorphisms
PEPT2 (most recently reviewed by ) is a sodium-independent symporter, or cotransporter, which catalyzes the electrogenic uphill transport of L-enantiomers of di- and tripeptides in a sequence-independent manner. Peptide translocation is coupled with the movement of H+, and the transmembrane electrochemical proton gradient provides the driving force.
The best-understood physiological role of PEPT2 is the reabsorption of di- and tripeptides from the glomerular filtrate. PEPT2 is also important in the reabsorption of peptide-like drugs (e.g. aminocephalosporins, ACE inhibitor prodrugs, antiviral nucleoside prodrugs) and endogenous non-dietary peptides (e.g. 5-aminolevulinic acid, carnosine).
The physiological significance of PEPT2 in other tissues has mainly been studied in preclinical models. Pept2 knockout mice appear phenotypically normal, but show diminished capacity for renal reabsorption of di- and tri- peptides, and diminished uptake of Gly-Sar through the choroid plexus [6, 7]. A study in mice showed that PEPT2 ablation considerably increased the brain extracellular fluid and cerebrospinal fluid levels of the β-lactam antibiotic cefadroxil . In rat astroglia-rich primary cultures and a neuroendocrine cell line, Pept2-mediated uptake of Cys-Gly was demonstrated, implying a role for Pept2 in signal transmission and redox homeostasis in the brain . In addition, in rat choroid plexus primary cultures, the active uptake of brain-derived peptides was shown. Therefore, Pept2 may play a role in the active clearance of peptide compounds from the CSF into the choroid plexus ,. In a bovine mammary gland cell model, Pept2 mRNA levels varied with lactogenic hormone levels, suggesting Pept2 involvement in milk formation . In an ex vivo human lung study, uptake of a model PEPT2 substrate from the airway lining fluid into lung epithelial cells was demonstrated , implying a role for this transporter in facilitating pulmonary absorption of inhaled peptide-based drugs.
PEPT2 can be inhibited by colistin and polymyxin B, last-resort therapeutics used to treat multi-drug resistant gram-negative bacterial infections .
No reports of DDIs due to PEPT2 inhibition have been posted thus far. Because of this, PEPT2 is not regarded as a likely candidate for DDI liabilities. PEPT2 appears to have a similar specificity to PEPT1, and drug substrates include cephalosporin and penicillin β-lactam antibiotics, ACE inhibitors, and antiviral nucleoside prodrugs. Given the tissue distribution of PEPT2, a role in renal re-absorption and CNS exposure may be postulated; however, the clinical relevance for PEPT2 substrates has not been thoroughly evaluated [14-16].
As DDIs are not reported or anticipated, there are no recommendations for PEPT2 transporter investigation in either the FDA or EMA guidance.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|kidney, choroid plexus||di- and tripeptides||
|β-lactam antibiotics, ACE-inhibitors, valganciclovir, carnosine, alafosfalin, polymyxins, bestatin, arphamenine A, arphamenine B||
cefadroxil, captopril, losartan,
1. Kamal, M.A., R.F. Keep, and D.E. Smith, Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharmacokinet, 2008. 23(4): p. 236-42.
2. Daniel, H. and G. Kottra, The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch, 2004. 447(5): p. 610-8.
3. Groneberg, D.A., et al., Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. Am J Physiol Endocrinol Metab, 2002. 282(5): p. E1172-9.
4. Groneberg, D.A., et al., Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake. Am J Pathol, 2001. 158(2): p. 707-14.
5. Viennois, E., et al., Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol, 2018. 8(2): p. 731-760.
6. Rubio-Aliaga, I., et al., Targeted disruption of the peptide transporter Pept2 gene in mice defines its physiological role in the kidney. Mol Cell Biol, 2003. 23(9): p. 3247-52.
7. Shen, H., et al., Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus. J Biol Chem, 2003. 278(7): p. 4786-91.
8. Chen, X., et al., Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study. Biochem Pharmacol, 2017. 131: p. 89-97.
9. Dringen, R., B. Hamprecht, and S. Broer, The peptide transporter PepT2 mediates the uptake of the glutathione precursor CysGly in astroglia-rich primary cultures. J Neurochem, 1998. 71(1): p. 388-93.
10. Shu, C., et al., Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture. J Pharmacol Exp Ther, 2002. 301(3): p. 820-9.
11. Zhou, M.M., et al., Effects of tripeptides and lactogenic hormones on oligopeptide transporter 2 in bovine mammary gland. J Anim Physiol Anim Nutr (Berl), 2011. 95(6): p. 781-9.
12. Groneberg, D.A., et al., Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung. Thorax, 2002. 57(1): p. 55-60.
13. Lu, X., et al., Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins. J Antimicrob Chemother, 2016. 71(2): p. 403-12.
14. Ganapathy, M.E., et al., Differential recognition of beta -lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2. J Biol Chem, 1995. 270(43): p. 25672-7.
15. Shu, C., et al., Mechanism of intestinal absorption and renal reabsorption of an orally active ace inhibitor: uptake and transport of fosinopril in cell cultures. Drug Metab Dispos, 2001. 29(10): p. 1307-15.
16. Dantzig, A.H., Oral absorption of beta-lactams by intestinal peptide transport proteins Adv Drug Deliv Rev, 1997. 23(1): p. 63-76.
17. Biegel, A., et al., The renal type H+/peptide symporter PEPT2: structure-affinity relationships. Amino Acids, 2006. 31(2): p. 137-56.