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.

针对多种药物抗性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着小分子。我们有助于开发新方法和 访问生物学和药用相关性的小分子的策略，并将其用作探测工具 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和两个的未来指示 我们设想使用19F NMR合并到配体 - 发现平台中的看似不同的程序。之一 我们的研究计划的重点领域是具有引人入胜的化学反应性投资组合的氟烯烃 主要是由于极性反转特征。我们正在研究氟化的极性反转特性 我们认识到的烯烃将解决氟化杂环的长期存在的区域选择性问题 化合物。我们的工作证明了FA在产生氮的区域选择性访问方面的适用性 含有氟化的杂环。另一个研究领域的重点是寻求新的化学工具和 解决阻碍抗生素的抗生素抗性菌株进化的创新策略 治疗并使它们无效，在医疗保健行业上付出了沉重的代价。我们目前正在探测 MRAY酶是细胞壁合成的关键组成部分，使用基于常规结构的理性设计 靶向蛋白质降解和基于19f NMR的配体的策略和非常规的发现平台 筛选。 R35 MIRA奖将有助于实现我们的目标，并使我们的两项研究合并 主题。这些研究的成功完成将使我们能够在获得对洞察力的见解方面做出了广泛的贡献 使用氟化探针，小分子抑制抗菌靶标的功能，结构和机制 DEGRADERS和19F基于NMR的筛选平台。这些研究将导致使用新化学物质的抗菌物 具有新颖的作用机制的实体，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 在整个美国和国际上。该研究计划将帮助参与的毕业生，以及 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。