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，包括心血管疾病和代谢疾病。 疾病，以及石棺减少症。越来越多的证据表明，辅因子NAD+和 依赖NAD+的蛋白质如sirtuins的活性与衰老和发育过程密切相关 慢性病。虽然许多研究都在探索含sirtuin的营养补充剂的健康益处 激活剂和NAD+前体已经取得了令人鼓舞的临床前结果，目前还没有药物 直接作用于NAD+代谢的候选人。拟议的研究项目的目标是开发 烟酰胺磷酸转移酶(NAMPT)的有效激活剂，NAMPT是催化该速率的酶 限制NAD+合成的步骤，并评估其逆转衰老相关生理功能障碍的能力 临床前小鼠模型。尽管先前的研究已经证实NAMPT的激活可以有年龄- 延缓和预防疾病的作用，目前还没有可用的疗法针对调节NAMPT 活动本身。这项拟议的研究解决了获取此类候选药物的关键限制， 这是缺乏一种有效的、选择性的和经过机械验证的铅分子来激活NAMPT 良好的吸收、分布、代谢和排泄(ADME)特征。要访问这样的化合物，请在 在本应用程序的R21阶段，我们建议开发和筛选一种专注于NAMPT的DNA编码的 化学库和使用计算机药物发现方法将筛选命中提升为有效的铅 候选化合物。NAMPT激活剂的有效性将通过体外试验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相将首先包括 先导候选化合物的综合药代动力学研究，以确定适当的剂量和 体内研究的给药途径。然后，将利用铅化合物来评估 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，用于开发一流的治疗药物，直接针对 一系列慢性病的衰老相关途径。从长远来看，这类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.