Tools to Study Electrophilic Stress and Develop Covalent Drugs

研究亲电应力和开发共价药物的工具

• 批准号: 10222732
• 负责人: Raphael Franzini
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222732
• 关键词: 4 hydroxynonenal; Atherosclerosis; Biology; DNA; Development; Diet; Disease; Ensure; Environment; Etiology; Foundations; Generations; Goals; Hand; Health; Homeostasis; Human; Inflammation; Libraries; Link; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolism; Methodology; Methods; Mission; Nerve Degeneration; Organism; Oxidative Stress; Pathologic; Pharmaceutical Preparations; Positioning Attribute; Proteins; Public Health; Research; Resistance; Role; Scientist; Solid; Stress; Technology; Testing; Time; United States National Institutes of Health; adduct; chemical reaction; disability; disorder prevention; inhibitor/antagonist; innovation; novel therapeutics; programs; screening; tool

Abstract Reactive electrophile species constantly modify biomolecules and impact human health in ways that are still poorly understood. This research program establishes the methodological groundwork to rigorously test hypotheses regarding reactive electrophilic species and to develop new covalent irreversible drugs. Bioactive electrophiles such as α,β-unsaturated carbonyls are present in the environment and diet, but they are also produced endogenously during metabolism and oxidative stress. They have been linked to the etiology of diverse pathological states such as atherosclerosis, cancer, neurodegeneration, and inflammation. Understanding the roles of reactive electrophilic species in homeostasis and disease will provide important guidance for disease prevention and the development of new therapeutics. However, a lack of research tools has impeded such endeavors and many studies in this field lack experimental rigor. The problem is that these reactive electrophilic species irreversibly modify a large number of biomolecules with very little control by the scientist. The program will close critical methodological gaps in the research on the effects of electrophiles in biology. Anticipated deliverables are methods that enable the controlled generation of such electrophiles at specific times and locations. Furthermore, methods to controllably reverse the formed covalent adducts of such electrophiles will be developed. Additionally, screening technologies to develop molecules that target specific protein residues will be established. The methods are innovative because they allow answering important biomedical questions that are currently out of reach. The program’s preliminary studies have established a solid foundation to achieve these goals. We have developed chemical reactions that allow generating α,β-unsaturated carbonyls on-demand in living systems, and we have established DNA-encoded libraries for the discovery of bioactive species. With these unique capabilities in hand, the research program is in the position to advance the understanding of reactive electrophilic species in biology and their impact on disease. To demonstrate their utility, we will apply them to study the involvement of 4-hydroxynonenal in atherosclerosis and study the dynamics of adaptive states associated with resistance to KRASG12C inhibitors of pancreatic cancer. We will take steps to ensure that the developed methods will be available to a broad range of scientists to maximize the impact of the program.

抽象的 反应性亲电子物质不断改变生物分子并以至今仍存在的方式影响人类健康 不太了解。该研究计划为严格测试奠定了方法论基础 关于反应性亲电物质的假设并开发新的共价不可逆药物。生物活性 α,β-不饱和羰基等亲电子试剂存在于环境和饮食中，但它们也 在新陈代谢和氧化应激过程中内源性产生。它们与多种疾病的病因有关 病理状态，如动脉粥样硬化、癌症、神经变性和炎症。了解 反应性亲电子物种在稳态和疾病中的作用将为疾病提供重要指导 预防和新疗法的开发。然而，研究工具的缺乏阻碍了这种研究 该领域的努力和许多研究缺乏实验严谨性。问题是这些反应性亲电子 物种不可逆地改变大量生物分子，而科学家几乎无法控制。该计划 将弥补生物学中亲电试剂影响研究中的关键方法论差距。预期的 可交付成果是能够在特定时间控制生成此类亲电子试剂的方法，并且 地点。此外，可控地逆转此类亲电子试剂形成的共价加合物的方法将 得到开发。此外，开发针对特定蛋白质残基的分子的筛选技术将 被成立。这些方法具有创新性，因为它们可以回答重要的生物医学问题 目前遥不可及。该计划的初步研究为实现这一目标奠定了坚实的基础 这些目标。我们开发了可按需生成 α,β-不饱和羰基的化学反应 在生命系统中，我们已经建立了 DNA 编码库来发现生物活性物种。和 掌握这些独特的能力，该研究计划能够促进对 生物学中的反应性亲电物种及其对疾病的影响。为了展示它们的实用性，我们将应用 他们研究 4-羟基壬烯醛在动脉粥样硬化中的作用并研究适应状态的动态 与胰腺癌 KRASG12C 抑制剂的耐药性相关。我们将采取措施确保 开发的方法将可供广大科学家使用，以最大限度地发挥该计划的影响。