Small molecule approach to activate human SIRT5

激活人类 SIRT5 的小分子方法

• 批准号: 10443067
• 负责人: Yana Cen
• 金额: $ 36.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443067
• 关键词: Acetylation; Achievement; Activation Analysis; Allosteric Regulation; Animal Model; Apoptosis; Archaea; Binding; Binding Sites; Biochemical; Biogenesis; Biological; Biological Assay; Biological Process; Biology; Biophysics; Caloric Restriction; Calories; Calorimetry; Cardiac health; Cardiovascular Diseases; Catalytic Domain; Cell physiology; Cells; Chemicals; Complement; Coupled; DNA Repair Gene; Data; Deacetylase; Deacetylation; Detection; Development; Diabetes Mellitus; Disease; Docking; Electrostatics; Enzyme Activation; Enzyme Kinetics; Enzymes; Family; Gene Dosage; Gene Silencing; Goals; Health; Health Benefit; High Pressure Liquid Chromatography; Human; Intake; Investigation; Knowledge; Lead; Libraries; Ligands; Light; Longevity; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Mitochondria; Modification; Molecular; Mus; Nature; Neurodegenerative Disorders; Neurons; Niacinamide; Nucleic Acid Regulatory Sequences; Organic Synthesis; Organism; Outcome; Pathology; Pharmaceutical Preparations; Photoaffinity Labels; Physiological; Play; Prevention; Protein Array; Proteins; Purine-Nucleoside Phosphorylase; Regulation; Role; SIRT1 gene; Series; Sir2-like Deacetylases; Sirtuins; Site-Directed Mutagenesis; Specificity; Stimulus; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Titrations; Tumor Suppressor Proteins; Work; X-Ray Crystallography; Yeasts; activity-based protein profiling; age related; analog; base; cell growth regulation; cellular targeting; design; dihydronicotinamide; enzyme activity; experimental study; fly; improved; in vitro Assay; in vitro testing; in vivo; innovation; insight; insulin secretion; interest; mutant; next generation; nicotinamide-beta-riboside; novel; novel therapeutics; preservation; rational design; response; riboside; scaffold; screening; small molecule; small molecule therapeutics; synthetic peptide; therapeutic candidate; tool

ABSTRACT The “magnificent seven” human sirtuins play critical roles in various cellular processes including DNA repair, gene silencing, mitochondrial biogenesis, insulin secretion and apoptosis. They regulate a wide array of protein and enzyme targets through their NAD+-dependent deacetylase activities. Sirtuins are also thought to mediate the beneficial effects of low calorie intake to extend longevity in diverse organisms from yeast to mammals. Small molecules mimicking calorie restriction to stimulate sirtuin activity are attractive therapeutics against age-related disorders such as cardiovascular diseases, diabetes and neurodegenerative diseases. Little is known about one of the mitochondrial sirtuins, SIRT5. SIRT5 has emerged as a critical player in maintaining cardiac health and neuronal viability upon stress, and functions as tumor suppressor in a context specific manner. Much has been debated about whether SIRT5 has evolved away from being a deacetylase because of its weak catalytic activity, especially in the in vitro testing. We have, for the first time, identified a SIRT5-selective allosteric activator, nicotinamide riboside (NR). It can increase SIRT5 deacetylation efficiency with different synthetic peptide substrates as well as its endogenous cognate substrate. However, the deacylase activity of SIRT5 is insensitive to NR activation. Mechanism of activation will be further explored in three specific aims. In aim 1, our effort will be directed at the elucidation of structural determinants required for the differential NR sensitivities and the identification of allosteric binding site. In aim 2, target engagement and activation of SIRT5 in response to activator treatment in the cellular context will be investigated. In aim 3, several series of SIRT5 activators will be synthesized based on our initial screening, structure-activity relationship analysis and docking studies using a combination of chemical and enzymatic strategies. The knowledge gained in the proposed study will not only clarify our understanding of the biological functions of SIRT5, but also lead to new therapeutics for metabolic disorders and age-related diseases.

摘要 人类的“七大”sirtuins在包括DNA在内的各种细胞过程中发挥着关键作用 修复、基因沉默、线粒体生物合成、胰岛素分泌和细胞凋亡。他们管理着一系列的 蛋白质和酶的目标通过其NAD+依赖性脱乙酰酶活性。Sirtuins也被认为 介导低热量摄入的有益影响，以延长从酵母到 哺乳动物模拟卡路里限制以刺激sirtuin活性的小分子是有吸引力的治疗方法 针对与年龄相关的疾病，如心血管疾病、糖尿病和神经退行性疾病。小 已知有一种线粒体sirtuins，SIRT 5。SIRT 5已经成为维持 心脏健康和神经元活力，并以特定的方式作为肿瘤抑制因子。 关于SIRT 5是否已经从脱乙酰酶进化而来，因为它的弱功能， 催化活性，特别是在体外测试中。我们首次鉴定了SIRT 5选择性变构蛋白， 激活剂，烟酰胺核苷（NR）。采用不同的合成方法可以提高SIRT 5的脱乙酰效率， 肽底物以及其内源性同源底物。然而，SIRT 5的脱酰酶活性是 对NR激活不敏感。激活机制将进一步探讨在三个具体目标。在目标1中， 我们的工作将集中在阐明不同的NR敏感性所需的结构决定因素上， 别构结合位点的鉴定。在目标2中，靶向SIRT 5的参与和激活，以响应 将研究细胞环境中的活化剂处理。在目标3中，将开发几个系列的SIRT 5激活剂。 合成基于我们的初步筛选，结构-活性关系分析和对接研究，使用 化学和酶促策略的组合。在拟议的研究中获得的知识不仅将 阐明了我们对SIRT 5生物学功能的理解，也为代谢性疾病的治疗带来了新的方法。 疾病和与年龄有关的疾病。