Regiospecific, Controlled Synthesis of Structurally Defined Peptide Scaffolds

结构明确的肽支架的区域特异性、受控合成

• 批准号: EP/J015989/1
• 负责人: Steven Cobb
• 金额: $ 12.73万
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ015989%2F1
• 关键词: Regiospecific; Controlled; Synthesis; Structurally; Defined

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.

蛋白质之间的非共价相互作用是所有生命系统中传递和处理信息的基本手段，因此蛋白质之间的相互作用是在细胞水平上调节生命的基础。自然结合伴侣的破坏或特定蛋白质表达水平的改变可以扰乱这一信号传导过程的平衡，并导致一系列疾病的发生。蛋白质-蛋白质相互作用的改变存在于癌症、艾滋病毒和阿尔茨海默氏症中，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，尽管进行了大量的研究，确定疾病相关蛋白-蛋白相互作用的抑制剂已被证明是非常具有挑战性的。在大多数蛋白质-蛋白质相互作用中存在的大结合表面意味着基于小分子的有效抑制剂很难识别，但是更大的化合物，如可用于模拟蛋白质结合表面的环肽，已经成为一种有前途的治疗方法。该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被设计成允许同时靶向蛋白质界面上的多个结合区域。但是，利用这种方法设计新的蛋白质相互作用抑制剂的进展受到缺乏可行的多环肽支架合成途径的严重阻碍。利用新型氟吡啶氨基酸作为关键构建块，我们将开发合成策略来获取多环肽支架，每个支架都具有明确的三维结构。所开发的方法还将允许以高度控制和区域特异性的方式形成肽支架，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-蛋白质相互作用抑制剂，从而开发针对癌症等疾病的新药物分子。

项目成果

Synthesis, Ni(II) Schiff base complexation and structural analysis of fluorinated analogs of the ligand (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPB)

配体 (S)-2-[N-(N-苄基脯氨酰)氨基]二苯甲酮 (BPB) 氟化类似物的合成、Ni(II) 席夫碱络合和结构分析

• DOI: 10.1016/j.jfluchem.2015.02.007
• 发表时间: 2015
• 期刊: Journal of Fluorine Chemistry
• 影响因子: 1.9
• 作者: Tatum N

A mild method for the synthesis of a novel dehydrobutyrine-containing amino acid

一种合成新型含脱氢丁酸氨基酸的温和方法

• DOI: 10.1016/j.tet.2014.05.031
• 发表时间: 2014
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Webster A