Synthesis and Evaluation of a Dipeptide-Drug Conjugate Library As Substrates for PEPT1.

The oligopeptide transporter PEPT1 is considered-as a valuable target (or prodrug design, but its 3D structure and substrate speificity of PEPT1 are not fully understood. In tins study, we designed, a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chemistry. Over 60 candidate structures containing various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overerxpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compounds selected to have medium or high affinity were tested for tbeir in vivo transport in a single-pass intestinal perfusion experiment. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development. [ABSTRACT FROM AUTHOR]