Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome

拟议研究的目的是开发一种新型分子，以验证一种称为去泛素化酶（DUB）的酶家族作为肿瘤学治疗靶点，并为启动抗癌药物发现计划提供先导化合物。dub通过从其他蛋白质中去除被称为泛素的小调节蛋白，在细胞中发挥重要作用。人类基因组编码大约80个去泛素化酶（DUB/DUB样）。该酶家族包含五个亚家族，其中四个已被研究和靶向。剩下的一组被称为锌依赖性dub，由于缺乏可用于探测其功能的分子，它们尚未成为目标。我们已经在各自的研究领域（Echalier -结构生物学，Jamieson -肽化学和Kessler -蛋白质质谱）建立了一个专家团队，以酶的天然肽底物为基础开发这些分子。利用现代合成化学技术，我们的目标是生产一系列分子，以前所未有的选择性靶向锌依赖性dub。从这些实验中获得的见解将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。

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.