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
基本信息
- 批准号:10028701
- 负责人:
- 金额:$ 30.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:4 hydroxynonenalAtherosclerosisBiologyDNADevelopmentDietDiseaseEnsureEnvironmentEtiologyFoundationsGenerationsGoalsHandHealthHomeostasisHumanInflammationLibrariesLinkLocationMalignant NeoplasmsMalignant neoplasm of pancreasMetabolismMethodologyMethodsMissionNerve DegenerationOrganismOxidative StressPathologicPharmaceutical PreparationsPositioning AttributeProteinsPublic HealthResearchResistanceRoleScientistSolidStressTechnologyTestingTimeUnited States National Institutes of Healthadductchemical reactiondisabilitydisorder preventioninhibitor/antagonistinnovationnovel therapeuticsprogramsscreeningtool
项目摘要
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.
摘要
项目成果
期刊论文数量(0)
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Raphael Franzini其他文献
Raphael Franzini的其他文献
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{{ truncateString('Raphael Franzini', 18)}}的其他基金
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 - 财政年份:2020
- 资助金额:
$ 30.5万 - 项目类别:
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:
10404013 - 财政年份:2020
- 资助金额:
$ 30.5万 - 项目类别:
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:
10619019 - 财政年份:2020
- 资助金额:
$ 30.5万 - 项目类别:
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