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)是对全球健康最严重的威胁之一，有可能使手术和化疗等挽救生命的医学进步变得如此危险，以至于不切实际。如果AMR损害了医疗程序并缩短了预期寿命，即使是神经退行性疾病等老年疾病也可能成为不那么重要的优先事项。新抗生素的缺乏加剧了AMR的挑战，人们普遍认识到迫切需要具有新作用机制的新分子。双功能分子在人类疾病中的研究兴趣激增，但在AMR中的应用还很少。蛋白水解靶向嵌合体(PROTAC)将目标蛋白招募到蛋白酶体机器中进行降解。与传统的抑制剂相比，PROTAC具有优势：活性不需要完全的靶标占据，这意味着一个双功能分子可以降解多个靶标蛋白质分子；由于需要靶标合成来恢复功能，因此可以实现更长的作用时间。我们最近首次证明了大肠杆菌周质蛋白水解酶DegP可以降解功能性的β-内酰胺酶TEM116，并合成了DegP和β-内酰胺酶的配体。此外，我们建立了一个自动合成PROTAC的平台，以快速生成细菌PROTAC，以探索构效关系。因此，本项目的目的是开发抗生素耐药酶的细菌PROTAC降解物。这将通过以下目标来实现：1.DegP和BET-内酰胺酶配体的SAR优化2。修改细菌PROTAC接头长度以降解细菌裂解物中的TEM116，3.细胞渗透的优化，降解其他β-内酰胺酶的图谱，并展示TEM116在完整细菌中的概念验证降解本项目的潜在应用和好处是广泛的。首先，这将提供一系列新的分子，具有新的作用机制，使耐药细菌对β-内酰胺类抗生素敏感，为继续翻译做好准备。其次，这开辟了一个新的研究领域，现有的抗生素可以转化为细菌的PROTAC，与新的或现有的抗生素合作以延长寿命，并且与抗药性酶抑制剂相比，靶向降解可能产生更强的效果。第三，高通量PROTAC生成的自动化合成平台可能会加速其他疾病的PROTAC的发展。