PepT1

PepT1 (SLC15A1) is a 708-amino-acid proton-coupled transmembrane symporter expressed predominantly on the apical brush-border membrane of intestinal enterocytes, with secondary expression in renal tubular epithelium. It uses the inward-directed proton gradient maintained by Na⁺/H⁺ exchangers to drive transport of di- and tripeptides into the cell against their concentration gradient, accommodating a broad substrate range that includes most natural di-/tripeptide combinations and several pharmaceutically important peptidomimetic drugs (notably the β-lactam antibiotics cefadroxil and cephalexin, the ACE inhibitor enalapril, and the antiviral valaciclovir). PepT1 is the principal molecular reason small peptides can achieve any meaningful oral bioavailability — direct paracellular absorption is otherwise negligible for charged molecules above ~500 Da, and most peptides are extensively hydrolysed by luminal and brush-border peptidases before reaching the basolateral surface. In peptide research, PepT1 is mechanistically relevant to KPV (an α-MSH-derived tripeptide whose colonic uptake is partly PepT1-mediated and exploited by hyaluronic-acid nanoparticle encapsulation strategies), to oral peptide-drug delivery research more broadly, and to the gut-inflammation literature where PepT1 expression is upregulated in inflammatory bowel disease and contributes to luminal antigen handling.