Development of native ion mobility mass spectrometry methods to study PROTAC systems

开发用于研究 PROTAC 系统的天然离子淌度质谱方法

• 批准号: 2483482
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2483482
• 关键词: Development; native; ion; mobility; mass

Small molecule inhibitors have traditionally been developed to bind to a specific protein, thereby preventing it from carrying out its function in the cell. In recent biotechnological approaches, molecules have been created that degrade a target protein, rather than inhibit it. Major advantages of protein degraders over inhibitors are the longer-lasting effects of degraders and the lower concentrations required to achieve efficacy. Moreover, degraders are applicable to a wider spectrum of proteins since binding is not limited to a specific active site. The most popular type of degraders to date are called proteolysis targeting chimeras (PROTACs), which are bifunctional ligands that bind simultaneously to the targeted protein and an E3 ligase, bringing the proteins into a complex, so that the E3 ligase labels the targeted protein for degradation by the cell. PROTACs have been developed against a variety of medically relevant proteins, such as the tumorigenic Androgen Receptor and Estrogen Receptor, as explored in clinical trials. A current limitation in the development of novel PROTACs is the ability to directly measure the formation of three-component complexes in a fast and efficient manner. Native mass spectrometry (nMS) is an efficient method for analysing the species present in complex mixtures involving E3 ligases, PROTACs, and substrate proteins. This is due to its ability to report on multiple binding stoichiometries present in dynamic protein mixtures, including species populated to a low extent. When coupled with ion mobility, which is a complementary gas-phase technique, different conformations of proteins or protein complexes can also be separated. The aim of this PhD project is to further develop native ion mobility mass spectrometry methods for the analysis of PROTACs and other protein degraders, which have strong potential as therapies for cancer and other diseases.

传统上开发小分子抑制剂是为了与特定蛋白质结合，从而阻止其在细胞中发挥其功能。在最近的生物技术方法中，已经创建了降解目标蛋白而不是抑制它的分子。与抑制剂相比，蛋白质降解剂的主要优点是降解剂的作用更持久，并且实现功效所需的浓度更低。此外，降解剂适用于更广泛的蛋白质，因为结合不限于特定的活性位点。迄今为止最流行的降解剂类型称为蛋白水解靶向嵌合体 (PROTAC)，它们是双功能配体，可同时与目标蛋白质和 E3 连接酶结合，将蛋白质形成复合物，以便 E3 连接酶标记目标蛋白质以供细胞降解。 PROTAC 是针对多种医学相关蛋白质而开发的，例如临床试验中探索的致瘤性雄激素受体和雌激素受体。目前新型 PROTAC 开发的一个限制是能够快速有效地直接测量三组分复合物的形成。天然质谱 (nMS) 是分析涉及 E3 连接酶、PROTAC 和底物蛋白的复杂混合物中存在的物质的有效方法。这是因为它能够报告动态蛋白质混合物中存在的多种结合化学计量，包括人口密度较低的物种。当与离子淌度（一种补充气相技术）结合使用时，也可以分离蛋白质或蛋白质复合物的不同构象。该博士项目的目的是进一步开发用于分析 PROTAC 和其他蛋白质降解剂的天然离子淌度质谱方法，这些方法在治疗癌症和其他疾病方面具有强大的潜力。