Abstract
d-Asp-Ala, a metabolically stable dipeptide, possesses a relatively high affinity for the Caco-2 oligopeptide transporter ( IC 50 = 5.75 ± 0.09 mM) as demonstrated by its ability to compete with [ 14c]Gly-Sar in cellular uptake experiments. When the β-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 [ 14c]GlySar binding to the oligopeptide transporter, i.e., IC so values for d-Asp(OcHx)-Ala and d-Asp(OBzl)-Ala were 2.80 ± 0.11 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 degradation for up to 5 h when incubated in the apical media of confluent Caco-2 monolayers. These results demonstrate that it is possible to covalently modify the side chain of one amino acid in an enzymatically stabilized dipeptide with small, aromatic molecules while enabling them to retain their affinity for the oligopeptide transporter.
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