Small molecule approach to activate human SIRT5

激活人类 SIRT5 的小分子方法

• 批准号: 10609089
• 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/10609089
• 关键词: Acetylation; Achievement; Activation Analysis; Allosteric Regulation; 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; 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; Libraries; Ligands; 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; cell growth regulation; cellular targeting; design; dihydronicotinamide; enzyme activity; experimental study; fly; halogenation; improved; in vitro Assay; in vitro testing; in vivo; innovation; insight; insulin secretion; interest; model organism; mutant; next generation; nicotinamide-beta-riboside; novel; novel therapeutics; preservation; rational design; response; riboside; scaffold; screening; small molecule; small molecule therapeutics; structural determinants; 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