Improving healthspan through discovery of potent NAMPT activators from a DNA-encoded library

通过从 DNA 编码库中发现有效的 NAMPT 激活剂来改善健康寿命

• 批准号: 10697352
• 负责人: Anthony John Donato
• 金额: $ 23.01万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697352
• 关键词: ADP Ribose Transferases; ATP Hydrolysis; Address; Age; Aging; Animal Model; Animals; Antihypertensive Agents; Biochemical; Biological Assay; Cardiovascular Diseases; Cell Line; Cells; Cellular Assay; Chemicals; Chronic Disease; Computing Methodologies; Coupling; Custom; DNA; DNA Damage; Deacetylase; Development; Diabetes Mellitus; Diphosphates; Disease; Dose; Drug Kinetics; Elderly; Enzymes; Equilibrium; Etiology; Excretory function; Functional disorder; Glucose; Goals; Health Benefit; Histidine; In Vitro; Inflammation; Lead; Libraries; Link; Lipids; Measures; Metabolic Diseases; Metabolism; Methods; Morbidity - disease rate; Mus; Nerve Degeneration; Niacinamide; Nicotinamide Mononucleotide; Outcome; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Phosphorylation; Physiological; Pre-Clinical Model; Process; Property; Proteins; Publications; Reaction; Research; Research Project Grants; Resistance; Risk Factors; Role; Route; Sirtuins; Stress; Structure; Testing; Therapeutic; Tissues; Translational Research; absorption; age related; aged; appropriate dose; burden of illness; cell type; cofactor; design; drug candidate; drug discovery; efficacy evaluation; functional decline; healthspan; improved; in vitro Assay; in vivo; innovation; lead candidate; middle age; mitochondrial dysfunction; mortality; mouse model; nicotinamide phosphoribosyltransferase; nutritional supplementation; pre-clinical; preclinical study; prevent; sarcopenia; screening; small molecule libraries

Abstract Advancing age is a primary risk factor for numerous chronic diseases including cardiovascular and metabolic diseases, as well as sarcopenia. Increasing evidence suggests that the levels of the cofactor NAD+ and the activity of NAD+-dependent proteins such as sirtuins have close links to the process of aging and development of chronic diseases. While many studies exploring the health benefit of nutritional supplementation with sirtuin activators and NAD+-precursors have had encouraging preclinical results, there are currently no drug candidates that directly act on NAD+-metabolism. The objective of the proposed research project is to develop a potent activator of nicotinamide phosphorybosyltransferase (NAMPT), the enzyme that catalyzes the rate limiting step in NAD+ synthesis, and to evaluate its ability to reverse age-related physiological dysfunction in a preclinical mouse model. Although previous studies have established that NAMPT activation can have age- delaying and disease-preventing effects, no currently available therapeutics are directed at modulating NAMPT activity per se. The proposed research addresses the key limitation towards accessing such drug candidates, which is the lack of a potent, selective, and mechanistically validated lead molecules for NAMPT activation with a favorable absorption, distribution, metabolism and excretion (ADME) profile. To access such a compound, in the R21 phase of this application, we propose to develop and screen a NAMPT-focused DNA-encoded chemical library and to use computational drug discovery methods to advance screening hits into potent lead candidate compounds. The efficacy of NAMPT activators will be tested with in vitro assays and in three different cell lines. Once candidate compounds are identified, the R33 phase will consist, first of comprehensive pharmacokinetic studies in lead candidate compounds to determine the appropriate dose and route of administration for in vivo studies. The lead compound will then be utilized to assess the impact of treatment on physiological measures of healthspan in middle-aged and old mice. The project, if successful, will deliver preclinical lead compounds for the development of first-in-class therapeutics that directly target the aging-related pathways of a wide range of chronic diseases. In the long term, such drugs may help decrease the morbidity and mortality of geriatric patients.

抽象的 年龄增长是心血管和代谢等多种慢性疾病的主要危险因素 疾病，以及肌肉减少症。越来越多的证据表明，辅因子 NAD+ 和 NAD+依赖性蛋白质（例如sirtuins）的活性与衰老和发育过程密切相关 慢性疾病。虽然许多研究都在探索用 Sirtuin 补充营养的健康益处 激活剂和NAD+前体已取得令人鼓舞的临床前结果，目前尚无药物 直接作用于 NAD+ 代谢的候选药物。拟议研究项目的目标是开发 烟酰胺磷酸核糖基转移酶 (NAMPT) 的有效激活剂，该酶催化速率 NAD+合成的限制步骤，并评估其逆转与年龄相关的生理功能障碍的能力 临床前小鼠模型。尽管之前的研究已经证实 NAMPT 激活可能会影响年龄 延迟和预防疾病的作用，目前没有针对调节 NAMPT 的治疗方法 活动本身。拟议的研究解决了获取此类候选药物的关键限制， 这是缺乏有效的、选择性的和机制验证的先导分子来激活 NAMPT 良好的吸收、分布、代谢和排泄 (ADME) 特征。要获得这样的化合物，在 在该应用的R21阶段，我们建议开发和筛选以NAMPT为重点的DNA编码 化学库并使用计算药物发现方法将筛选结果推进为有效的先导化合物 候选化合物。 NAMPT 激活剂的功效将通过体外测定和三种方法进行测试 不同的细胞系。一旦确定了候选化合物，R33 相将包括： 对先导候选化合物进行全面的药代动力学研究，以确定适当的剂量和 体内研究的给药途径。然后，先导化合物将用于评估 中老年小鼠健康寿命生理指标的治疗。该项目如果成功，将 提供临床前先导化合物，用于开发直接靶向的一流疗法 多种慢性疾病的衰老相关途径。从长远来看，此类药物可能有助于减少 老年患者的发病率和死亡率。