Chemical development of a cyclic peptide protein-protein interaction inhibitor.

环肽蛋白质-蛋白质相互作用抑制剂的化学开发。

• 批准号: 1792813
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1792813
• 关键词: Chemical; development; cyclic; peptide; protein

The rapid growth of tumours results in their outstripping of the supply of oxygen and nutrients delivered by the existing vascular network. As a result, tumours need to adapt to hypoxia (low environmental oxygen). This process is primarily mediated through the hypoxia inducible factor (HIF-1), a heterodimeric transcription factor composed of an alpha and beta subunit that alters the expression of over 300 genes in response to the onset of hypoxia. A second isoform, HIF-2alpha also binds to HIF-1beta and is thought to adaptation to long term hypoxia. This project aims to use the tools of medicinal chemistry to optimise a series of cyclic peptide HIF-1 and HIF-2 inhibitors towards the clinic. We will synthesize a series of non-natural analogues of the leading hit molecule. The potency of these molecules will be assessed by a variety of biophysical techniques, and these results will in turn inform on the structure of additional molecules in an attempt to increase potency. We will also attempt to obtain structural data on the peptide/protein complex to enable design of small molecule inhibitors binding into the same pocket. By taking this two-pronged approach, we hope to develop the next generation of potent, small molecule HIF inhibitors.

肿瘤的快速生长导致它们超出了现有血管网络输送的氧气和营养的供应。因此，肿瘤需要适应缺氧（低环境氧）。这一过程主要通过缺氧诱导因子（HIF-1）介导，HIF-1是一种异二聚体转录因子，由α和β亚基组成，在缺氧发生时改变300多个基因的表达。第二种亚型hif - 2α也与hif - 1β结合，并被认为能适应长期缺氧。本项目旨在利用药物化学的工具对一系列环肽HIF-1和HIF-2抑制剂进行临床优化。我们将合成一系列非天然的先导分子类似物。这些分子的效力将通过各种生物物理技术进行评估，这些结果将反过来为试图增加效力的其他分子的结构提供信息。我们还将尝试获得肽/蛋白质复合物的结构数据，以便设计结合到相同口袋的小分子抑制剂。通过采取这种双管齐下的方法，我们希望开发出下一代有效的小分子HIF抑制剂。