New methods in peptide mimicry

多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。目前有40多种多肽在全球上市，约有270种多肽处于临床试验阶段，约有400种处于晚期临床前阶段(马克思，V.《看着多肽类药物长大》化学。&Eng.2005年3月14日新闻，第83卷(11)，第17-24页)。从基因组学和蛋白质组学的丰硕研究中，一个基于多肽的药物制剂的新时代正在出现。然而，多肽结构的固有缺陷需要开发新的工具来研究多肽相互作用和具有改进的药理性质的新的多肽模拟物以克服进入临床所需的障碍。这就是基于多肽的新药的情况，例如用于治疗前列腺癌的GnRH拮抗剂Zoladex，通过在C末端残基加入氮杂氨基酸，使其对酶代谢更具抵抗力。同样，治疗糖尿病的新药塞姆林含有一种天然存在的人类多肽荷尔蒙--胰淀素的合成类似物。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，以及用于对抗对当前药物具有抗药性的微生物的新型抗菌剂。然而，从多肽到药物的过程特别具有挑战性，需要解剖天然多肽的诊断工具来提供信息，以重建受体识别和信号转导所需的元件。这项建议的重点是创建这样的工具，并使用它们来构建与原生肽相比具有更高效力、更高的代谢稳定性和更好的生物利用度的模拟物。由于作为药物发现先导结构的多肽的数量持续增长，拟议中的创建多肽模拟物的新策略的研究将为未来新药、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.