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.

摘要