Investigation of peptides and peptidomimetics for developing bioactive molecules

肽或蛋白质的小片段为开发高灵敏度的分子和生物诊断、具有特异性相互作用和与许多生物分子结合的传感器、潜在的药物、抑制剂和食品防腐剂开辟了巨大的可能性。 然而，天然α-肽经常易受蛋白质水解和代谢的影响，其中它们可以在生物活性环境中到达其靶标之前被其他生物实体“消耗”或“分解”。 模拟天然肽但在构象和代谢上更稳定的合成分子，例如β-肽，是天然肽的可行替代品。 这些非天然肽模拟物或肽模拟物可以提供与其靶生物系统的增强的相互作用。 拟议的研究的目标是：a）设计和合成代谢稳定和生物活性的肽模拟物;和B）开发新的方法来研究肽在各种体外系统的生物，分析和环境相关性的相互作用。 我们将使用自动化（机器人）固相合成来设计纤维素膜上的肽阵列。 α和β肽文库都将由氨基酸的合理组合合成。 将研究肽相互作用或肽结合中的三种基本重要情况。 首先，抗菌肽类似物将被设计、合成和测试以模拟IIa类和IIb类细菌素（它们是有效的抗菌肽）。 第二，将开发和测试基于SARS病毒受体蛋白的模型肽作为蛋白质-蛋白质相互作用抑制剂的实施方案。 第三，将开发用于鉴定与丙型肝炎病毒包膜蛋白的特异性相互作用的肽阵列，以鉴定最有效的进入抑制剂。 这三项研究将为合理的肽设计和合成提供一个基本的视角。 预计这项研究将提供一个基础广泛的平台，为未来发展的肽阵列作为一个可行的工具，用于制备新的支架的生物相互作用的高通量研究。

Peptides, or small fragments of proteins, have opened up immense possibilities for development of highly sensitive molecular and biological diagnostics, sensors with specific interaction and binding with numerous biomolecules, potential drugs, inhibitors, and food preservatives. However, natural alpha-peptides are frequently susceptible to proteolysis and metabolism, where they can be "consumed" or "broken down" by other biological entities before they reach their targets in a biologically active environment. Synthetic molecules that mimic natural peptides, but are conformationally and metabolically more stable, such as beta-peptides, are viable alternatives to natural peptides. These unnatural peptide-mimics or peptidomimetics can provide enhanced interaction with their target biological systems. The objectives of the proposed research are: a) design and synthesis of metabolically stable and biologically active peptidomimetics; and b) development of new methods to study peptide interactions in a variety of in vitro systems of biological, analytical, and environmental relevance. We will use automated (robotic) solid phase synthesis to design peptide arrays on cellulose membranes. Both alpha and beta peptide libraries will be synthesized from rational combinations of amino acids. Three scenarios of fundamental importance in peptide interactions or peptide binding will be studied. First, antibacterial peptide analogues will be designed, synthesized, and tested to mimic class IIa and IIb bacteriocins (which are potent antimicrobial peptides). Second, a model peptide based on a SARS virus receptor protein will be developed and tested as an embodiment of protein-protein interaction inhibitor. Third, a peptide array for identifying specific interactions with a Hepatitis C virus envelope protein will be developed to identify the most potent entry inhibitor. These three studies will provide a fundamental perspective of rational peptide design and synthesis for targeted applications. It is expected that this research will provide a broad-based platform for future development of peptide arrays as a viable tool for preparation of novel scaffolds for high-throughput studies of biological interactions.