High-throughput development of bacterial PROTACs

细菌 PROTAC 的高通量开发

• 批准号: MR/Y503484/1
• 负责人: Thomas Lanyon-Hogg
• 金额: $ 30.9万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY503484%2F1
• 关键词: throughput; development; bacterial; PROTACs

Antimicrobial resistance (AMR) is one of the most serious threats to global health, potentially making life-saving medical advances such as surgery and chemotherapy so dangerous as to be impractical. Even diseases of old age such as neurodegeneration may become a lessening priority if AMR compromises medical procedures and curtails life expectancy. The challenge of AMR is exacerbated by a scarce pipeline of new antibiotics and it is widely appreciated that new molecules with novel mechanisms of action are urgently needed.Bifunctional molecules have seen an explosion of research interest in human diseases; however, use in AMR is lacking. Proteolysis-targeting chimeras (PROTACs) recruit target proteins to the proteasome machinery for degradation. PROTACs have advantages over traditional inhibitors: activity does not require complete target occupancy meaning one bifunctional molecule can degrade multiple target protein molecules; and a longer duration of action can be achieved as target synthesis is required to recover function. We have recently shown for the first time that the E. coli periplasmic protease DegP can degrade functional beta-lactamase enzyme TEM116, and have synthesised ligands for both DegP and beta-lactamases. In addition, we have established a platform for automated PROTAC synthesis to rapidly generate bacterial PROTACs to explore structure-activity relationships.The aim of this project is therefore to develop bacterial PROTAC degraders of antibiotic resistance enzymes. This will be achieved through the following objectives:1. SAR optimisation of DegP and bet-lactamase ligands2. Modification of bacterial PROTACs linker lengths for degradation of TEM116 in bacterial lysates,3. Optimisation of cell penetration, profiling for degradation of other beta-lactamases, and demonstration of proof-of-concept degradation of TEM116 in intact bacteriaThe potential applications and benefits of this project are broad. Firstly, this will provide a new series of molecules with a novel mechanism of action to sensitize resistant bacteria to beta-lactam antibiotics, primed for continued translation. Secondly, this opens a new area of research where existing antibiotics may be converted to bacterial PROTACs to partner with new or existing antibiotics to prolong lifetime, and where target degradation may produce enhanced effects compared to resistance enzyme inhibitors. Thirdly, the automated synthesis platform for high-throughput PROTAC generation may accelerate development of PROTACs for other diseases.

抗菌素耐药性（AMR）是对全球健康的最严重威胁之一，有可能使诸如手术和化学疗法之类的挽救生命的医疗进步如此危险，以至于不切实际。如果AMR损害医疗程序并降低预期寿命，即使是老年疾病（例如神经退行性的疾病）也可能成为减少的优先事项。新抗生素的稀缺管道加剧了AMR的挑战，并广泛认为，迫切需要具有新型作用机制的新分子。功能性分子已经看到了人类疾病的研究兴趣爆炸。但是，缺乏在AMR中使用。涉及蛋白水解靶向嵌合体（Protac）将靶蛋白募集到蛋白酶体降解。与传统抑制剂相比，Protac具有优势：活性不需要完全的目标占用率，这意味着一个双功能分子可以降解多个靶蛋白分子。由于需要恢复功能的目标合成，因此可以实现更长的动作持续时间。我们最近首次表明，大肠杆菌周质蛋白酶DEGP可以降解功能性β-内酰胺酶TEM116，并具有合成的DEGP和β-内酰胺酶合成的配体。此外，我们已经建立了一个自动protac合成的平台，以快速生成细菌protac来探索结构活性关系。这将通过以下目标实现：1。 DEGP和BET-内酰胺酶配体的SAR优化。细菌protac接头长度的修饰，以降解细菌裂解物中TEM116的降解，3。细胞渗透的优化，其他β-内酰胺酶降解的分析，以及在完整细菌中TEM116的概念证明降解的证明，该项目的潜在应用和益处很广。首先，这将提供一系列新的分子，并具有一种新型的作用机理，可以使抗性细菌对β-内酰胺抗生素敏感，并进行持续翻译。其次，这打开了一个新的研究领域，现有的抗生素可以转化为细菌protac，以与新的或现有的抗生素合作以延长寿命，并且与抗性酶抑制剂相比，目标降解可能会产生增强的作用。第三，高通量Protac生成的自动合成平台可能会加速其他疾病的Protac。