Expanding the small molecule toolbox through novel applications of fluorinated alkenes

通过氟化烯烃的新颖应用扩展小分子工具箱

• 批准号: 10714822
• 负责人: Sudeshna Roy
• 金额: $ 28.68万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714822
• 关键词: Address; Alkenes; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Award; Bacterial Drug Resistance; Bacterial Infections; Biological; Cell Wall; Cellular Structures; Chemicals; Collaborations; Disparate; Environment; Enzymes; Evolution; Fostering; Future; Goals; Healthcare Industry; Heterocyclic Compounds; International; Learning; Ligands; Medicine; Methods; Multi-Drug Resistance; Nitrogen; Postdoctoral Fellow; Property; Research; Science; Structure; United States; Universities; Work; cost; fascinate; global health; graduate student; human disease; innovation; insight; multidisciplinary; new chemical entity; novel; programs; protein degradation; rational design; resistant strain; screening; skills; small molecule; tool; undergraduate student

New Methods and Chemical Tools Against Multi Drug-resistant Bacterial Infections ABSTRACT The central theme of our lab revolves around small molecules. We contribute to developing new methods and strategies to access small molecules of biological and medicinal relevance and using them as tools to probe biological questions or human diseases. This proposal outlines our ongoing efforts and future directions of two seemingly disparate programs that we envision merging into a ligand-discovery platform using 19F NMR. One of our research program's focus areas is on fluorinated alkenes with a fascinating chemical reactivity portfolio primarily due to the polarity inversion feature. We are investigating the polarity inversion property of fluorinated alkenes, which we recognize will solve the long-standing problem of regioselectivity in fluorinated heterocyclic compounds. Our work demonstrated the applicability of FAs in generating regioselective access to nitrogen- containing fluorinated heterocycles. The other research area is focused on seeking new chemical tools and innovative strategies to address the evolution of antibiotic-resistance strains that have impeded antibiotic treatment and rendered them ineffective, costing heavily on the healthcare industry. We are currently probing the MraY enzyme, a key component of cell wall synthesis, using conventional structure-based rational design strategy and unconventional discovery platforms of targeted protein degradation and 19F NMR-based ligand screening. An R35 MIRA award would help accomplish our goals and enable the merger of our two research themes. Successful completion of these studies will allow us to contribute broadly in gaining insights into the function, structure, and mechanism of inhibition of antibacterial targets using fluorinated probes, small-molecule degraders, and a 19F NMR-based screening platform. These studies will lead to antibacterials with new chemical entities with novel mechanism of action that are urgently needed to replenish our arsenal of new and existing antibiotics. An R35 MIRA award would also foster our existing and new collaborations within the university, across the United States, and internationally. This research program will help the participating graduate, and undergraduate students and postdoctoral scholars enhance and learn new skills in interdisciplinary sciences while working in a highly collaborative and multidisciplinary environment.

防治多重耐药细菌感染的新方法和新化学工具 摘要 我们实验室的中心主题是围绕小分子展开的。我们为开发新的方法和 获取与生物和医学相关的小分子并将其用作工具进行探测的策略 生物问题或人类疾病。这份建议概述了我们正在进行的努力和两个方面的未来方向 我们设想使用19F核磁共振将看似完全不同的程序合并到一个配体发现平台中。其中之一 我们的研究计划的重点领域是具有迷人的化学反应组合的氟化烯 主要是由于极性反转功能。我们正在研究含氟化合物的极性反转性质 烯烃，我们认识到它将解决长期存在的含氟杂环的区域选择性问题 化合物。我们的工作证明了FA在产生区域选择性地获取氮方面的适用性- 含有氟化杂环的。另一个研究领域是寻找新的化学工具和 解决阻碍抗生素的抗生素耐药菌株进化的创新战略 治疗并使其无效，给医疗保健行业带来了沉重的代价。我们目前正在调查 Mray酶，细胞壁合成的关键成分，使用传统的基于结构的合理设计 靶向蛋白质降解和~(19)F核磁共振配基的策略和非常规发现平台 放映。R35 Mira奖将有助于实现我们的目标，并使我们的两项研究能够合并 主题。成功完成这些研究将使我们能够作出广泛贡献，深入了解 含氟小分子探针抑制抗菌靶标的功能、结构及机理 降解剂和基于19F核磁共振的筛选平台。这些研究将导致使用新化学物质的抗菌药。 具有新的行动机制的实体，这些实体迫切需要补充我们的新的和现有的武器库 抗生素。R35 Mira奖还将促进我们在大学内部的现有合作和新的合作， 在全美和国际上。这项研究计划将帮助参与的毕业生，以及 本科生和博士后学者提高和学习跨学科科学的新技能 同时在高度协作和多学科的环境中工作。