Development and synthesis of molecular scaffolds for the manipulation of protein interactions and function

绝大多数蛋白质的细胞功能是通过与其他蛋白质的物理相互作用来实现的。这些蛋白质-蛋白质相互作用对于许多细胞和生物过程是必需的。因此，它们与化合物的操纵为发现新的治疗剂和开发创新的分子工具以提高我们对生化途径的理解提供了巨大的潜力。大多数蛋白质之间的相互作用发生在细胞内部。因此，对能够穿透细胞并选择性调节或破坏特定蛋白质-蛋白质相互作用的分子的需求正在迅速增加。该研究计划描述了开发工程肽模拟分子支架以结合靶蛋白并调节蛋白质相互作用和功能的新方法。这些分子能够模拟分子识别所需的不同蛋白质结构，并参与蛋白质-蛋白质相互作用。在第一部分中，大环类肽（N-取代甘氨酸）的合成作为潜在的拟肽支架和它们的结构行为和穿透细胞的能力进行了研究。类肽对蛋白酶不敏感，并且具有作为询问蛋白质功能的化学工具和作为治疗候选物的巨大潜力。关于它们的构象能力知之甚少，探索这些能力的系统研究具有极大的兴趣。第二部分描述了使用多组分反应在固体载体上一步制备杂环支架。在药物化学中，大量的特权结构是基于杂环的，并且它们模拟蛋白质二级结构的能力已经被证明。所提出的方法是非常灵活的，并允许产生具有高分子多样性的库。最后，多组分反应还将用于偶联肽片段以合成大的多肽。这种方法将提供各种感兴趣的生物活性多肽，以研究蛋白质功能并开发治疗剂。蛋白质配体和蛋白质-蛋白质相互作用调节剂的开发是基础研究和药物先导发现背景下的一个具有挑战性的重要目标。我们的工作将为肽模拟提供新的分子结构，并为操纵蛋白质相互作用和功能提供新的可能性。拟议的项目将对有机，医药和组合化学以及化学生物学和生命科学产生重大影响，因为蛋白质结合分子是潜在的药理学试剂，研究生物化学途径的分子工具，以及用于纯化或检测复杂混合物中蛋白质的蛋白质捕获剂。

The cellular functions of a vast majority of proteins are performed through physical interactions with other proteins. These protein-protein interactions are essential for many cellular and biological processes. Therefore, their manipulation with chemical compounds provides great potential for the discovery of novel therapeutic agents and the development of innovative molecular tools to improve our understanding of biochemical pathways. Most of these protein-protein interactions happen inside the cells. As a result, the demand for molecules that are able to penetrate cells and selectively modulate or disrupt specific protein-protein interactions is rapidly increasing.***This research proposal describes novel approaches for the development of engineerable peptidomimetic molecular scaffolds to bind target proteins and modulate protein interactions and functions. These molecules are able to mimic different protein structures required for molecular recognition and involved in protein-protein interactions.****In the first part, macrocyclic peptoids (N-substituted glycines) are synthesized as potential peptidomimetic scaffolds and their structural behaviours and abilities to penetrate cells are investigated. Peptoids are not sensitive to proteases and have a great potential both as chemical tools to interrogate protein functions and as therapeutics candidates. Very little is known about their conformational capabilities and a systematic study to explore these capabilities is of great interest.****The second part describes the use of a multicomponent reaction to prepare heterocyclic scaffolds on solid support in a single step. A great number of privileged structures in medicinal chemistry are based on heterocycles and their abilities to mimic protein secondary structures have been demonstrated. The proposed approach is very flexible and allows the generation of libraries with high molecular diversity. Finally, the multicomponent reaction will also be used to couple peptide fragments for the synthesis of large polypeptides. This approach will give access to a wide variety of bioactive polypeptides of interests to study protein functions and develop therapeutic agents.****The development of protein ligands and protein-protein interaction modulators is a challenging and important goal in the context of fundamental research and pharmaceutical lead discovery. Our work will give access to novel molecular structures for peptidomimicry and unfold new possibilities for manipulation of protein interactions and function. The proposed projects will have a strong impact in organic, medicinal and combinatorial chemistry as well as chemical biology and life sciences since protein-binding molecules are potential pharmacological agents, molecular tools to study biochemical pathways, and protein capture agents for the purification or detection of proteins in complex mixtures.***