Tools to Study Electrophilic Stress and Develop Covalent Drugs

摘要 反应性亲电物质不断地修饰生物分子，并以仍然存在的方式影响人类健康。 不太了解。这项研究计划建立了方法论基础，以严格测试 关于反应性亲电物质的假说和开发新的共价不可逆药物。生物活性 亲电体如α，β-不饱和羰基存在于环境和饮食中，但它们也 在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 反应性亲电物质在体内平衡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，缺乏研究工具阻碍了这一进程。 这一领域的努力和许多研究缺乏实验的严谨性。问题是，这些反应性亲电 物种不可逆转地改变了大量的生物分子，而科学家几乎无法控制。程序 将关闭关键的方法学差距的研究亲电体在生物学中的影响。预期 可交付成果是能够在特定时间控制生成此类亲电试剂的方法， 地点此外，可控地逆转所形成的这种亲电试剂的共价加合物的方法将 发展。此外，开发靶向特定蛋白质残基的分子的筛选技术将 建立。这些方法是创新的，因为它们可以回答重要的生物医学问题， 目前还遥不可及。该计划的初步研究奠定了坚实的基础， 这些目标。我们已经开发了允许按需生成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，用于发现生物活性物种。与 这些独特的能力在手，研究计划是在推进理解的位置， 生物学中的活性亲电物质及其对疾病的影响。为了证明它们的效用，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， 与胰腺癌对KRASG 12 C抑制剂的耐药性相关。我们会采取措施， 将向广大科学家提供所开发的方法，以最大限度地扩大该方案的影响。

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.