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

摘要 年龄增长是许多慢性疾病的主要危险因素，包括心血管和代谢性疾病。 疾病，以及肌肉减少症。越来越多的证据表明，辅因子NAD+和 NAD+依赖性蛋白如sirtuins的活性与衰老和发育过程有密切联系 慢性病的症状。虽然许多研究探索了sirtuin营养补充剂的健康益处， 激活剂和NAD+前体已经有了令人鼓舞的临床前结果，目前还没有药物 直接作用于NAD+代谢的候选物。拟议研究项目的目标是开发 一种烟酰胺磷酸核糖转移酶（NAMPT）的有效激活剂，该酶催化 NAD+合成的限制步骤，并评估其逆转年龄相关的生理功能障碍的能力， 临床前小鼠模型。虽然以前的研究已经确定NAMPT激活可以有年龄- 延迟和预防疾病的作用，目前没有可用的治疗方法是针对调节NAMPT 活动本身。拟议的研究解决了获得此类候选药物的关键限制， 这是缺乏一种有效的，选择性的，和机械验证的引导分子的NAMPT激活， 良好的吸收、分布、代谢和排泄（ADME）特征。为了进入这样一个化合物，在 在本申请的R21阶段，我们建议开发和筛选NAMPT聚焦的DNA编码的 化学库，并使用计算药物发现方法来推进筛选命中到有效的铅 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阶段将首先包括 对主要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， 用于体内研究的给药途径。然后，将利用先导化合物评估 对中老年小鼠健康寿命的生理指标进行处理。该项目如果成功， 提供临床前先导化合物，用于开发直接靶向 与衰老有关的多种慢性疾病的途径。从长远来看，这些药物可能有助于减少 老年患者的发病率和死亡率。

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.