PRODRUGS OF PEPTIDES OBTAINED BY DERIVATIZATION OF THE C-TERMINAL PEPTIDE-BOND IN ORDER TO EFFECT PROTECTION AGAINST DEGRADATION BY CARBOXYPEPTIDASES

Two N-Z-protected dipeptides were N-hydroxymethylated al the C-termina l peptide bond. The stability of the derivatives was investigated in a queous buffer solutions as a function of pH. The compounds degraded qu antitatively to their parent N-Z-protected dipeptide. The stability wa s also examined in buffer solutions containing different concentration s of carboxypeptidase A. It was shown that the half-lives of degradati on in buffer with and without carboxypeptidase A were of the same orde r. These results demonstrate that the enzymatic reactivity of CPA is i nfluenced if the C-terminal peptide bond is modified as it is here by N-hydroxymethylation. It is suggested that N-hydroxymethylation of the C-terminal peptide bond map become a useful approach to improve absor ption characteristics by reducing the enzymatic degradation of peptide s.