Regiospecific, Controlled Synthesis of Structurally Defined Peptide Scaffolds

蛋白质之间的非共价相互作用在所有生命系统中都被用作传递和处理信息的基本手段，因此蛋白质-蛋白质相互作用是在细胞水平上调节生命的基础。天然结合伙伴的破坏或特定蛋白质表达水平的改变可以扰乱这一信号过程的平衡，并导致一系列疾病的发生。在癌症、HIV和阿尔茨海默病中存在改变的蛋白质-蛋白质相互作用，抑制与这些疾病相关的异常蛋白质-蛋白质相互作用为开发高选择性药物分子提供了一条令人兴奋的新途径。然而，尽管做出了相当大的研究努力，但事实证明，寻找疾病相关蛋白质-蛋白质相互作用的抑制剂是非常具有挑战性的。大多数蛋白质-蛋白质相互作用中都存在较大的结合表面，这意味着基于小分子的有效抑制剂很难识别，但较大的化合物，如可用于模拟蛋白质结合表面的环肽，已成为一种有希望的治疗先导。这一领域的前沿是多环肽支架的应用，因为这些化合物的三维结构可以设计成允许同时针对蛋白质界面上的多个结合区域。但是，由于缺乏可行的合成多环肽支架的路线，使用这种方法设计新的蛋白质相互作用抑制剂的进展严重受阻。利用新的氟吡啶氨基酸作为关键的构建单元，我们将开发合成策略来获得多环肽支架，每个支架都具有定义的三维结构。开发的方法还将允许以高度受控和区域特定的方式形成多肽支架，这是目前使用现有技术无法实现的。获得多环肽支架将有助于加速发现蛋白质-蛋白质相互作用的抑制剂，从而开发针对癌症等疾病的新药物分子。

Noncovalent interactions between proteins are used in all living systems as an essential means of transferring and processing information and as such protein-protein interactions are fundamental to regulating life on a cellular level. Disruption of natural binding partners or alterations in the expression levels of a particular protein can perturb the balance of this signaling process and lead to the onset of a range of diseases. Altered protein-protein interactions are present in cancers, HIV, and Alzheimer's and inhibiting the abnormal protein-protein interactions associated with these diseases offers an exciting new avenue to develop highly selective drug molecules. However, despite considerable research efforts, identifying inhibitors of disease-associated protein-protein interactions has proven to be very challenging. The large binding surfaces present in most protein-protein interactions has meant that effective inhibitors based on small molecules have been hard to identify, but larger compounds, such as cyclic peptides that can be used to mimic protein binding surfaces, have emerged as a promising therapeutics leads. At the cutting edge of this field is the application of multicyclic peptide scaffolds, as the 3-dimensional structure of these compounds can be designed to allow multiple binding regions on a protein interface to be targeted simultaneously. But progress into designing new inhibitors of protein-protein interactions using this approach is severely hampered by a lack of viable synthetic routes to multicyclic peptide scaffolds. Utilising novel fluoropyridine amino acids as the key building blocks we will develop synthetic strategies to access multicyclic peptide scaffolds, each with a defined 3-dimensional structure. The methodology developed will also permit the formation of the peptide scaffolds in a highly controlled and regionspecific manner which is something that is not currently possible using existing technologies. Having access to multicyclic peptide scaffolds will help to accelerate the discovery of inhibitors of protein-protein interactions and thus the development of new drug molecules to target diseases such as cancer.