VIP FAMILY PEPTIDE ANALOGS--GH, INSULIN, GLUCAGON

血管活性肠肽、促胰液素、胰高血糖素、胃 抑制性多肽(GIP)和最近的PHI，生长激素 释放激素(GRF)与垂体腺苷环化酶激活 多肽(PACAP)是一个不断增长的多肽家族的成员，这些多肽 控制许多胃肠道、胰腺和内分泌事件。 尽管每个肽的序列同源性非常接近，但它们 展现出完全不同的生物活性光谱。因此，一个 这项提案的主要目的之一仍然是划定 那些负责受体结合的分子特征 通过检查组织结构变化对组织的影响 具体细节。另一个重要目标是开发用于 增加受体亲和力和对蛋白水解性的抵抗 以增强治疗潜力。这些设计方法将 然后用于开发有效的竞争性受体 拮抗剂随后被用来探测各种生物 内源性多肽的功能。在过去，这个项目发现 GRF、VIP和分泌素的第一受体拮抗剂。主要研究 未来的突破口将是VIP和促胰液素拮抗剂的增强 目前较弱的潜力，以及对新的PACAP的SAR研究 多肽和GIP(1-30)片段，以期评估其 药理特性和发展中的受体拮抗剂。其中一些 这些多肽及其类似物具有潜在的治疗作用。 意义。最近，针对65岁以上男性的生长激素替代疗法 被证明可以逆转衰老的一些影响，而且可能是最好的实现 在临床水平上，通过使用高度有效的GRF类似物。潜力 生长激素水平升高在癌症和术后体重增加中的作用 病人也是一种可能性。一种有效的胰升糖素受体的使用 GIP对糖尿病患者胰岛素释放的拮抗剂作用 已经被注意了很多年。VIP在哮喘患者中的应用 虽然目前不太成功，但可能会更有前途 一种更稳定的酶类似物，在这方面，PACAP应该 也要考虑。分泌素的竞争性受体拮抗剂可以 对治疗急性胰腺炎有用，而且有可能 促胰液素可能是某些肿瘤类型的生长因子也提示 其拮抗剂的潜在治疗作用。VIP受体是 存在于许多类型的肿瘤组织中，这种多肽还可能具有 对肿瘤细胞生长的调节作用可被一种 对抗者。PACAP肽的有趣的组织出现(例如， 各种血管床、中枢神经系统、精子)提示临床应用 这些和它们的受体拮抗剂也可能出现。GIP是 与胰岛素释放机制有关的类似物可能有 在糖尿病治疗中的作用。

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.