Boosting NAD+ with a small molecule that activates NAMPT
Boosting NAD+ with a small molecule that activates NAMPT
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DOI：
10.1038/s41467-019-11078-z
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发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Pinkerton, Anthony B.
中科院分区：
文献类型：
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作者：
Gardell, Stephen J.;Hopf, Meghan;Pinkerton, Anthony B.
促进细胞内 NAD(+) 的药理学策略因其治疗潜力而备受瞩目。一种方法是激活烟酰胺磷酸核糖基转移酶 (NAMPT) 以增加烟酰胺单核苷酸 (NMN) 的产生，NMN 是哺乳动物细胞中主要的 NAD(+) 前体。 NAMPT 激活剂的高通量筛选和命中先导活动产生了 SBI-797812，这是一种结构类似于活性位点定向 NAMPT 抑制剂的化合物，可阻断这些抑制剂与 NAMPT 的结合。 SBI-797812 将 NAMPT 反应平衡转向 NMN 形成，增加 NAMPT 对 ATP 的亲和力，稳定磷酸化 NAMPT His247，促进焦磷酸副产物的消耗，并减弱 NAD(+) 的反馈抑制。 SBI-797812 的这些作用使 NAMPT 成为一种“超级催化剂”，可以更有效地生成 NMN。用 SBI-797812 处理培养的细胞会增加细胞内 NMN 和 NAD(+)。给小鼠服用 SBI-797812 会升高肝脏 NAD(+)。 SBI-797812 等小分子 NAMPT 激活剂是提高细胞内 NAD(+) 并实现其相关有益作用的开创性方法。
Pharmacological strategies that boost intracellular NAD(+) are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD(+) precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD(+). These effects of SBI-797812 turn NAMPT into a "super catalyst" that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD(+). Dosing of mice with SBI-797812 elevates liver NAD(+). Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD(+) and realize its associated salutary effects.