Development of PACAP38 analogue with improved stability: physicochemical and in vitro/in vivo pharmacological characterization.

Pituitary adenylate cyclase activating polypeptide 38 (PACAP38), one of the major peptide transmitters, has emerged as a promising drug candidate for the treatment of type 2 diabetes. In the present study, on the basis of previous structure-activity relationships, a new PACAP38 derivative, [R(15, 20, 21), L(17)]-PACAP38, was chemically synthesized with the aim of enhancing the therapeutic potential of PACAP38. The solution structure of the new derivative was almost identical to that of PACAP38 as evaluated by circular dichroic spectroscopy, and both PACAP38 and the new derivative stimulated adenylate cyclase in rat insulinoma RIN-m5F cells with EC(50) values of 4.6 and 5.5 nM, respectively. Stability studies revealed the gradual degradation of PACAPs in rat serum, although there appeared to be a 42% reduction in degradation kinetics for [R(15, 20, 21), L(17)]-PACAP38 compared with that of PACAP38. The novel derivative also exhibited more potent protective effects against streptozotocin (STZ)-induced apoptotic death of RIN-m5F cells, possibly due to the enhanced stability. The n0-STZ model, in which neonatal rats were injected with STZ at birth, developed a typical diabetic condition; however, chronic administration of [R(15, 20, 21), L(17)]-PACAP38 resulted in protection of pancreatic islets, followed by the improvement of glycemic control. Thus, the chemical modification of PACAP38 led to the development of a new promising derivative with enhanced stability and biological activity, and early administration of [R(15, 20, 21), L(17)]-PACAP38 might be of help for preventing the development of diabetes in type 2 diabetic model rats.