Peptidomimetics approaches for developing biologically active molecules

蛋白质和天然小肽通过与其他生物分子相互作用，在许多生物现象中起着关键作用，往往提供了很好的治疗途径。然而，天然蛋白质和多肽往往容易发生蛋白质分解和代谢，在到达目标之前，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，因此是可行的治疗替代品。这些非天然的多肽模拟物或多肽模拟物的折叠结构可以增强与生物系统的相互作用，就像具有稳定二级结构的天然多肽能够更好地促进某些相互作用一样。这项研究的目的是研究两个新的合成β-多肽家族之间的构效关系。这些β-肽将由易得的L-天冬氨酸和β-氨基-L-丙氨酸单体合成。在此背景下，将合成几种生物活性多肽的多肽和模拟多肽，如IIa类细菌素和SARS病毒受体蛋白的短肽序列，并研究它们的构象与活性的关系。设计代谢稳定的多肽仿制药的另一种方法是使用载体系统来输送有效的天然多肽，如细菌系统或脂质体。将利用细菌表达系统合成微球素J25的多肽类似物，以供输送。

Proteins and small natural peptides play a key role in many biological phenomena by interacting with other biomolecules, and often provide excellent therapeutic pathways. However, natural proteins and 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. Synthetic molecules that mimic natural peptides, but are conformationally and metabolically more stable, such as beta-peptides, are therefore viable alternatives as therapeutics. The folded structures of these unnatural peptide-mimics or peptidomimetics can provide enhanced interaction with the biological systems, just like the natural peptides with stable secondary structure facilitate some interactions better than others. The objective of the proposed research is to study structure-activity relationship among two new families of synthetic beta-peptides. These beta-peptides will be synthesized from easily accessible L-aspartic acid and beta-amino-L-alanine monomers. In this context, peptide and peptidomimetic analogs of several biologically active peptides such as class IIa bacteriocins and a short peptide sequence from SARS virus receptor protein, will be synthesized and the relationship of their conformation to activity will be studied. An alternate approach to the design of metabolically stable peptidomimetics is the use of a carrier system for the delivery of potent natural peptides, such as a bacterial system or liposomes. Peptide analogs of microcin J25 will be synthesized for delivery using a bacterial expression system.