Synthesis and Analysis of Peptide Hormone-based Prodrugs

摘要

Peptides represent a rich natural source of potential medicines with one notable pharmaceutical limitation being their relatively short duration of action. A particularly good example of this phenomenon is glucagon-like peptide 1 (GLP), a hormone of appreciable interest for the treatment of Type II diabetes. This is because GLP has been reported to enhance the endogenous secretion of insulin [1] only when blood glucose is elevated, significantly minimizing the risk of hypoglycemia. However, native GLP demonstrates an extremely short plasma half-life (~2 min) caused by the combined effect of rapid degradation by Dipeptidyl Peptidase IV (DPP-IV) and renal clearance [2]; along with a relatively narrow therapeutic index. Structure-function studies have shown that the Nterminal histidine is especially important for high potency of GLP [3]. Our work focuses on the assembly of GLP-prodrugs as a mean to extend the duration of action and broaden the therapeutic index. The design is directed at the conversion of GLP amide and ester prodrugs that differentially convert to the parent drug under physiological conditions, strictly by structural propensity for intramolecular cyclization of dipeptide-based amide/ester extensions. This conversion, driven by the inherent chemical instability of the prodrug eliminates the intrinsic variability in enzymatic cleavage within and across patient use. In a set of dipeptide extended GLP-analogs, we explored the rate of diketopiperazine (DKP) and diketomorpholine (DMP) formation, and the release of the active peptide at pH 7.2 and 37°C. These experimental conditions are virtually invariant in a chemical sense and should be translatable for use with other peptides where the N-terminus or the hydroxyl group (serine/threonine) is vital to bioactivity. Our goal is to identify a set of dipeptide prodrugs of different structures that might offer cleavage in the range 1 -200 hrs.