Investigation of peptides and peptidomimetics for developing bioactive molecules

多肽或蛋白质的小片段为高灵敏度的分子和生物诊断、与众多生物分子、潜在药物、抑制剂和食品防腐剂具有特定作用和结合的传感器的发展提供了巨大的可能性。然而，天然的α-肽往往容易被蛋白质分解和代谢，在生物活性环境中到达目标之前，它们可能会被其他生物实体“消耗”或“分解”。模拟天然多肽，但在构象和代谢上更稳定的合成分子，如β-多肽，是天然多肽的可行替代品。这些非天然的多肽模拟物或多肽模拟物可以增强与其目标生物系统的相互作用。拟议研究的目标是：a)设计和合成代谢稳定的生物活性多肽模拟物；b)开发新的方法来研究各种与生物、分析和环境相关的体外系统中的多肽相互作用。我们将使用自动化(机器人)固相合成来设计纤维素膜上的多肽阵列。α和β多肽库都将由氨基酸的合理组合来合成。将研究三种在多肽相互作用或多肽结合中具有基本重要性的场景。首先，将设计、合成和测试抗菌肽类似物，以模拟IIa和IIb类细菌素(这是一种有效的抗菌肽)。其次，将开发一种基于SARS病毒受体蛋白的模型肽，并将其作为蛋白质相互作用抑制物的体现进行测试。第三，将开发用于识别与丙型肝炎病毒包膜蛋白的特定相互作用的多肽阵列，以确定最有效的进入抑制物。这三项研究将为有针对性的应用提供一个合理的多肽设计和合成的基本视角。本研究有望为多肽阵列的未来发展提供一个基础广泛的平台，为高通量生物相互作用研究提供一种可行的新型支架制备工具。

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.