New methods in peptide mimicry

肽及其相关的模拟物都是当今临床有效的药物。突出的传统例子包括催产素、胰岛素、环孢素和鲑鱼降钙素，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，超过40种多肽在全球市场上销售，约270种多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。“看着多肽药物成长”化学。& Eng。新闻，2005年3月14日，83卷（11），第17-24页。从基因组学和蛋白质组学的丰富研究中，一个以肽为基础的药物制剂的新时代正在出现。然而，肽结构固有的缺陷需要开发新的工具来研究肽相互作用和具有改进药理学性质的新肽模拟物，以克服进入临床的必要障碍。以肽为基础的新药物就是这样，比如用于治疗前列腺癌的GnRH拮抗剂Zoladex，通过在c端残基上加入一个氮杂氨基酸，使其更能抵抗酶代谢。同样，治疗糖尿病的新药Symlin也含有一种人工合成的类似于自然产生的人类肽激素——胰淀素。未来有希望的基于多肽的药物包括针对各种癌症和疟疾的疫苗，以及对抗对现有药物具有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，并且需要解剖天然肽的诊断工具来为重建受体识别和信号转导所需的元素提供信息。本提案的重点是创建这样的工具和它们的使用来构建模拟具有更高的效力，增强代谢稳定性和提高生物利用度相对于天然肽。由于作为药物发现先导结构的多肽的数量不断增长，因此对创造多肽模拟物的新策略的拟议研究将为未来新药、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.