New methods in peptide mimicry

肽和更重要的是它们的相关模拟物，都是当今临床上有效的药物。 突出的传统例子包括催产素、胰岛素、环孢菌素和鲑鱼降钙素，它们分别广泛用于分娩、糖尿病、免疫抑制和骨质疏松症。目前，全球有超过40种肽上市，约270种肽处于临床阶段测试，约400种处于高级临床前阶段（马克思，V.“Watching Peptide Drugs Grow Up”Chem. & Eng. News Mar.14，2005，1983（11）pp. 17-24）。 一个新时代的肽为基础的药物制剂正在出现从肥沃的研究，基因组学和蛋白质组学。然而，肽结构的固有缺点需要开发用于研究肽相互作用的新工具和具有改善的药理学性质的新肽模拟物，以克服进入临床的必要障碍。 这种情况已经出现在新的肽类药物中，例如用于治疗前列腺癌的GnRH拮抗剂Zoladex，通过在C-末端残基掺入氮杂氨基酸，使其对酶代谢更具抗性。类似地，治疗糖尿病的新药Symlin含有天然存在的人类肽激素胰淀素的合成类似物。未来有希望的基于肽的药物包括针对各种癌症和疟疾的疫苗以及对抗对当今药物表现出耐药性的生物体的新型抗菌剂。 然而，从肽到药物的过程是特别具有挑战性的，并且需要用于解剖天然肽的诊断工具来提供用于重建受体识别和信号转导所需的元件的信息。 该提案集中于创建这样的工具及其用于构建相对于天然肽表现出更高效力、增强的代谢稳定性和改善的生物利用度的模拟物。由于作为药物发现的先导结构的肽的数量持续增长，因此拟议的关于创建肽模拟物的新策略的研究定位于为未来新药，生物聚合物和材料的生产提供有价值的见解和实用的线索。

Peptides and more importantly their related mimics, both serve as effective drugs in clinic today. Prominent traditional examples include oxytocin, insulin, cyclosporin and salmon calcitonin, which are widely used in childbirth, diabetes, immunosuppression and osteoporosis, respectively. At present more than 40 peptides are marketed worldwide, around 270 peptides are in clinical phase testing, and about 400 are in advanced preclinical phases (Marx, V. "Watching Peptide Drugs Grow Up" Chem. & Eng. News Mar. 14, 2005, Vol 83 (11) pp. 17-24). A new age of peptide-based pharmaceutical agents is emerging from fertile studies in genomics and proteomics. Inherent drawbacks to peptide structures have, however, required development of novel tools for studying peptide interactions and new peptide mimics with improved pharmacological properties to surmount the necessary hurdles to enter into clinic. Such has been the case for new peptide-based drugs, such as the GnRH antagonist Zoladex for treating prostate cancer, which was made more resistant to enzyme metabolism by incorporating an aza-amino acid at the C-terminal residue. Similarly, Symlin a new drug for the treatment of diabetes contains a synthetic analog of a naturally occurring human peptide hormone, amylin. Promising peptide-based drugs for the future include vaccines against various cancers and malaria as well as novel antimicrobial agents to fight organisms exhibiting resistance to present day drugs. The process from peptide to drug is, however, particularly challenging and diagnostic tools for dissecting the native peptide are required to furnish information for recreating elements required for receptor recognition and signal transduction. This proposal focuses on the creation of such tools and their use to construct mimics exhibiting higher potency, enhanced metabolic stability and improved biological availability relative to the native peptide. Because the number of peptides serving as lead structures for drug discovery continues to grow, the proposed research on new strategies for creating peptide mimics is positioned to provide valuable insight and practical leads for the future production of new drugs, biopolymers and materials.