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.

对抗多重耐药细菌感染的新方法和化学工具 抽象的 我们实验室的中心主题围绕小分子。我们致力于开发新方法和 获取具有生物和医学相关性的小分子并将其用作探测工具的策略 生物学问题或人类疾病。该提案概述了我们正在进行的努力以及两个项目的未来方向 我们设想将看似不同的程序合并到使用 19F NMR 的配体发现平台中。之一 我们的研究计划的重点领域是具有令人着迷的化学反应组合的氟化烯烃 主要是由于极性反转特性。我们正在研究氟化物的极性反转特性 烯烃，我们认为这将解决氟化杂环中长期存在的区域选择性问题 化合物。我们的工作证明了 FA 在区域选择性获取氮方面的适用性 含有氟化杂环。另一个研究领域专注于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策略 治疗并使它们无效，给医疗保健行业带来沉重代价。我们目前正在探索 MraY酶是细胞壁合成的关键成分，采用传统的基于结构的理性设计 靶向蛋白质降解和基于 19F NMR 的配体的策略和非常规发现平台 筛选。 R35 MIRA 奖项将有助于实现我们的目标并实现我们两项研究的合并 主题。成功完成这些研究将使我们能够为深入了解 使用氟化探针、小分子抑制抗菌靶标的功能、结构和机制 降解剂和基于 19F NMR 的筛选平台。这些研究将导致使用新化学物质的抗菌剂 具有新颖行动机制的实体，迫切需要补充我们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现有和新的合作， 遍及美国和国际。该研究计划将帮助参与的毕业生，并且 本科生和博士后学者增强和学习跨学科科学的新技能 在高度协作和多学科的环境中工作。