BETA-CARBOXYLIC ACID ESTERIFIED D-ASP-ALA RETAINS A HIGH-AFFINITY FORTHE OLIGOPEPTIDE TRANSPORTER IN CACO-2 MONOLAYERS

D-Asp-Ala, a metabolically stable dipeptide, possesses a relatively hi gh affinity for the Caco-2 oligopeptide transporter (IC50 = 5.75 +/- 0 .09 mM) as demonstrated by its ability to compete with [C-14]Gly-Sar i n cellular uptake experiments. When the beta-carboxylic acid of D-Asp- Ala is modified by esterification with a cyclohexyl group (D-Asp(OcHx) -Ala) or a benzyl group (D-Asp(OBzl)-Ala), the resulting compounds are still able to inhibit [C-14]Gly-Sar binding to the oligopeptide trans porter, i.e., IC50 values for D-Asp(OcHx)-Ala and D-Asp(OBzl)-Ala were 2.80 +/- 0.1 and 2.62 +/- 0.35 mM, respectively. HPLC analysis shows that both D-Asp(OcHx)-Ala and D-Asp(OBzl)-Ala are fully resistant to d egradation for up to 5 h when incubated in the apical media of conflue nt Caco-2 monolayers. These results demonstrate that it is possible to covalently modify the side chain of one amino acid in an enzymaticall y stabilized dipeptide with small, aromatic molecules while enabling t hem to retain their affinity for the oligopeptide transporter. (C) 199 7 Elsevier Science B.V.