强效且特异的线粒体 Sirtuins Sirt3 和 Sirt5 的激活剂。
Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5.
机构信息
Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy.
出版信息
J Med Chem. 2022 Oct 27;65(20):14015-14031. doi: 10.1021/acs.jmedchem.2c01215. Epub 2022 Oct 13.
Sirtuins are NAD-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.
Sirtuins 是依赖 NAD 的蛋白去酰基酶，参与代谢调节和与衰老相关的疾病。七种人类 Sirtuin 同工型的特异性激活剂将是重要的化学工具和有潜力的治疗药物。Sirt1 的激活剂已被描述，并通过该同工型的独特 N 端结构域发挥作用。对于大多数其他 Sirtuin 同工型，包括线粒体 Sirt3-5，尚未鉴定出有效的特异性激活剂。我们在这里描述了基于 1,4-二氢吡啶的化合物的鉴定和表征，这些化合物要么作为泛 Sirtuin 激活剂，要么特异性地刺激 Sirt3 或 Sirt5。这些激活剂与 Sirtuin 催化核心结合，不依赖 NAD 和酰化肽，并刺激肽和蛋白底物的周转。这些化合物还在调节细胞凋亡和电子传递链等的细胞系统中激活 Sirt3 或 Sirt5。我们的结果为有效的 Sirtuin 激活提供了一个支架，以及针对 Sirt3 和 Sirt5 的衍生物，这为进一步的药物开发提供了极好的基础。
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