PROTACS: new computational methods and targets

PROTACS：新的计算方法和目标

• 批准号: 2897704
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2897704
• 关键词: PROTACS; new; computational; methods; targets

PROtealysis TArgeting Chimeras, also designated PROTACs, are bifunctional molecules composed of two protein ligands connected by a linker. The ligand on one side binds to the E3-ubiquitin ligase, which targets a protein for degradation, while the other ligand binds the unwanted proteins that needs to be removed from the cell. Since PROTACs had first been described in 2001, the technology has been applied to an increasing range of targets, with the first cancer therapeutics now in clinical trials. All PROTACs are based on known ligands for an E3-ligase on one side, in many cases, the Von Hippel-Lindau tumor suppressor (VHL) connected to a known or novel ligand for the target protein. However, only recently, it has become clear that the length and chemistry of the linker, in most cases composed of polyethylene glycols, or alkyls, alkynes or triazoles, plays a major role in the biological activity of the PROTAC compound. With a virtually unlimited number of potential linkers, new computational methods are needed to guide and support the development of new PROTACs. In this collaboration with the Cambridge Crystallographic Data Centre (CCDC) we will develop molecular modelling tools for linker design that use the structures of the VHL ligase and the target protein in combination with empirical rules derived from successful linkers. These tools will initially be tested and validated using one well-established PROTACs model system, VHL bound to the human bromodomain 4 (Brd4), a major target for cancer therapies, where crystals structures of the ternary VHL-PROTAC-Brd4 complex have been determined. In parallel we will target the Eppstein-Barr virus nuclear antigen 1 (EBNA1), the key protein, consistently expressed in all human tumours that are linked to Eppstein-Barr viral infections. Several VHL and Brd4 ligands have been described in the literature and are commercially available. New PROTAC compound containing novel linkers will be synthesized in collaboration with the organic chemistry groups in the department. Binding to both, the VHL as well as the target protein, will be tested using the novel spectral-shift technology implemented in Nanotemper Dianthus screening. The high sensitivity of this techniques makes it particularly useful to investigate consecutive binding events in ternary systems in 384-well plate high-throughput format. The most promising compounds will be forwarded to our structural biology platform including crystallisation and crystal structure determination as well as cryo Electron Microscopy.

PROtealysis Targeting Chimeras，也称为PROTAC，是由两个蛋白质配体通过接头连接组成的双功能分子。一侧的配体结合E3-泛素连接酶，其靶向蛋白质进行降解，而另一个配体结合需要从细胞中去除的不需要的蛋白质。自2001年PROTAC首次被描述以来，该技术已被应用于越来越多的靶点，目前第一种癌症疗法已进入临床试验。所有PROTAC都是基于一侧的E3-连接酶的已知配体，在许多情况下，Von Hippel-Lindau肿瘤抑制因子（VHL）连接到靶蛋白的已知或新配体。然而，直到最近，已经清楚的是，在大多数情况下由聚乙二醇或烷基、炔或三唑组成的接头的长度和化学性质在PROTAC化合物的生物活性中起主要作用。由于潜在的连接子数量几乎无限，因此需要新的计算方法来指导和支持新PROTAC的开发。在与剑桥晶体数据中心（CCDC）的合作中，我们将开发用于连接器设计的分子建模工具，该工具使用VHL连接酶和靶蛋白的结构，并结合来自成功连接器的经验规则。这些工具最初将使用一个完善的PROTAC模型系统进行测试和验证，该模型系统是与人类溴结构域4（Brd 4）结合的VHL，该模型系统是癌症治疗的主要靶标，其中已经确定了三元VHL-PROTAC-Brd 4复合物的晶体结构。同时，我们将靶向Eppstein-Barr病毒核抗原1（EBNA 1），这是一种关键蛋白，在与Eppstein-Barr病毒感染相关的所有人类肿瘤中始终表达。几种VHL和Brd 4配体已经在文献中描述并且是可商购的。新的PROTAC化合物含有新的连接器将合成与部门的有机化学组合作。将使用NanotemperDianthus筛选中实施的新型光谱位移技术测试与VHL和靶蛋白的结合。该技术的高灵敏度使得其特别适用于以384孔板高通量格式研究三元系统中的连续结合事件。最有前途的化合物将被转发到我们的结构生物学平台，包括结晶和晶体结构测定以及低温电子显微镜。