TY - JOUR T1 - Human PEPT1 pharmacophore distinguishes between dipeptide transport and binding. AU - Vig,Balvinder S, AU - Stouch,Terry R, AU - Timoszyk,Julita K, AU - Quan,Yong, AU - Wall,Doris A, AU - Smith,Ronald L, AU - Faria,Teresa N, PY - 2006/6/9/pubmed PY - 2006/8/1/medline PY - 2006/6/9/entrez SP - 3636 EP - 44 JF - Journal of medicinal chemistry JO - J Med Chem VL - 49 IS - 12 N2 - The human intestinal oligopeptide transporter (PEPT1) facilitates the absorption of dipeptides, tripeptides, and many peptidomimetic drugs. In this study, a large number of peptides were selected to investigate the structural features required for PEPT1 transport. Binding affinity was determined in a Gly-Sar uptake inhibition assay, whereas functional transport was ranked in a membrane depolarization assay. Although most of the peptides tested could bind to PEPT1, not all were substrates. As expected, single amino acids and tetrapeptides could not bind to or be transported by PEPT1. Dipeptide transport was influenced by charge, hydrophobicity, size, and side chain flexibility. The extent of transport was variable, and unexpectedly, some dipeptides were not substrates of PEPT1. These included dipeptides with two positive charges or extreme bulk in either position 1 or 2. Our results identify key features required for PEPT1 transport in contrast to most previously described pharmacophores, which are based on the inhibition of transport of a known substrate. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16759105/Human_PEPT1_pharmacophore_distinguishes_between_dipeptide_transport_and_binding_ DB - PRIME DP - Unbound Medicine ER -