Vasoactive intestinal polypeptide (VIP), secretin, glucagon, gastric inhibitory polypeptide (GIP) and, most recently, PHI, growth hormone releasing hormone (GRF) and pituitary adenylate cyclase activating peptide (PACAP) are members of an ever growing family of peptides which control numerous gastrointestinal, pancreatic and endocrine events. Although sequence homologies are very close for each peptide, they exhibit entirely different spectra of biological activities. Thus, one of the main aims of this proposal continues to be the delineation of those molecular features which are responsible for receptor binding from tissue to tissue by examining the effects of structural changes on specificities. Another important aim is to develop methods for increasing receptor affinity and resistance to proteolytic hydrolysis in order to enhance therapeutic potential. These design approaches will then be used for the development of potent competitive receptor antagonists which are subsequently used to probe the various biological functions of endogenous peptides. In the past, this project discovered the first receptor antagonists of GRF, VIP, and secretin. Major research thrusts in the future would be enhancement of VIP and secretin antagonist potencies which are presently weak, and SAR studies on the new PACAP peptides and the GIP(1-30) fragment with a view towards evaluating their pharmacological properties and developing receptor antagonists. Some of these peptides and their analogues have potential therapeutic significance. GH replacement therapy in men over 65 has been recently shown to reverse some effects of aging and can perhaps best be achieved at a clinical level by use of highly potent GRF analogues. The potential of enhanced GH levels in aiding weight gain in cancer and postoperative patients is also a possibility. The use of a potent glucagon receptor antagonist or the insulin-releasing effects of GIP in diabetic patients has been noted for many years. The use of VIP in asthmatic patients, whilst not being too successful at present, might be more promising with an enzymatically more stable analogue and in this regard, PACAP should also be considered. A competitive receptor antagonist of secretin could be of use in treating acute pancreatitis and the possibility that secretin may be growth factor in some tumor types also suggests a potential therapeutic role for its antagonists. VIP receptors are present in many types of tumor tissue and this peptide may also have a regulatory role in tumor cell growth which could be blocked with an antagonist. The interesting tissue occurrences of PACAP peptides (e.g., various vascular beds, CNS, spermatozoa) suggest that clinical uses for these and their receptor antagonists could also emerge. GIP is implicated in the mechanisms of insulin release and analogues may have a role in the treatment of diabetes.
Showing the most recent 10 out of 17 publications
