Small molecule approach to activate human SIRT5

激活人类 SIRT5 的小分子方法

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 “七大”人类沉默调节蛋白在包括 DNA 在内的各种细胞过程中发挥着关键作用修复、基因沉默、线粒体生物发生、胰岛素分泌和细胞凋亡。 Sirtuins 也被认为通过其 NAD+ 依赖性脱乙酰酶活性发挥作用。介导低热量摄入的有益影响，以延长从酵母到多种生物体的寿命模拟热量限制来刺激去乙酰化酶活性的小分子是有吸引力的治疗方法。预防心血管疾病、糖尿病和神经退行性疾病等与年龄相关的疾病。众所周知，SIRT5 是一种线粒体去乙酰化酶，它已成为维持线粒体功能的关键角色。压力下的心脏健康和神经活力，并以特定的方式发挥肿瘤抑制作用。关于 SIRT5 是否由于其较弱的功能而不再是一种脱乙酰酶，一直存在很多争论。催化活性，特别是在体外测试中，我们首次鉴定了 SIRT5 选择性变构。激活剂烟酰胺核苷（NR）可以通过不同的合成提高SIRT5的脱乙酰效率。肽底物及其内源同源底物然而，SIRT5 的脱酰酶活性是。在目标 1 中，我们将进一步探讨对 NR 激活不敏感的激活机制。我们将努力阐明不同的 NR 敏感性所需的结构决定因素和目标 2 中变构结合位点的识别，SIRT5 的靶标参与和激活。在目标 3 中，将研究细胞环境中的激活剂治疗。基于我们的初步筛选、构效关系分析和对接研究，使用在拟议的研究中获得的知识不仅会结合化学和酶策略。澄清了我们对 SIRT5 生物学功能的理解，同时也带来了新的代谢疗法失调和与年龄有关的疾病。