Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome

COP9 信号体的底物拟肽抑制剂 (SPI)

• 批准号: EP/N034260/2
• 负责人: Aude Echalier-Glazer
• 金额: $ 24.2万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FN034260%2F2
• 关键词: Substrate; Peptidomimetic; Inhibitors; SPIs; COP9

The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme.DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function.We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.

这项拟议研究的目的是开发一种新型的分子，它将允许验证称为脱泛素酶(DUB)的一系列酶作为肿瘤学的治疗靶点，并提供先导化合物来启动抗癌药物发现计划。DUB通过从其他蛋白质中去除称为泛素的小调节蛋白，在细胞中发挥主要作用。人类基因组编码了大约80种脱泛素酶(DUB/DUB样)。该酶家族包括五个亚家族，其中四个已被研究和靶向。剩下的一组被称为依赖锌的DUBS，由于缺乏可用于探索其功能的分子，因此没有成为靶点。我们已经建立了一个专家团队，在他们方面的研究领域(Echalier-结构生物学，Jamieson-多肽化学和Kessler-蛋白质质谱仪)开发基于酶的天然多肽底物的此类分子。利用现代合成化学技术，我们的目标是以前所未有的选择性生产一系列针对依赖锌的DUB的分子。从这些实验中获得的见解将被用于验证它们作为治疗靶点，并为选择性DUB抑制剂的基于结构的药物设计提供信息。

项目成果

Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc Amino Acids Incorporating Zinc-Binding Groups

• DOI: 10.1021/acs.orglett.9b00885
• 发表时间: 2019-05-03
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Mahindra, Amit;Millard, Christopher J.;Jamieson, Andrew G.
• 通讯作者: Jamieson, Andrew G.

Enzymatically-stable oxetane-based dipeptide hydrogels.

酶稳定的氧杂环丁烷二肽水凝胶。

• DOI: 10.1039/c7cc09701h
• 发表时间: 2018
• 期刊: Chemical communications (Cambridge, England)
• 作者: McDougall L