State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
Talanta. 2024 Jul 1;274:125975. doi: 10.1016/j.talanta.2024.125975. Epub 2024 Mar 27.
Sirtuin1 (SIRT1), an NAD-dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ. This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH was synthesized by modifying the surface of UiO-66-NH with Ni ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC value of 0.95 ± 0.12 μM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders.
Sirtuin1 (SIRT1)，一种依赖 NAD 的组蛋白去乙酰化酶，在调节分子信号通路方面发挥着关键作用。最近，抑制 SIRT1 而不是激活 SIRT1 显示出对中枢神经系统疾病的治疗潜力，然而，已发现的 SIRT1 抑制剂仍然有限。在这项工作中，开发了一种基于双重识别的策略，从天然资源中就地筛选 SIRT1 抑制剂。该方法利用 Ni 修饰的金属有机骨架 (Ni@Tyr@UiO-66-NH) 与含有工程化 His 标记 SIRT1 蛋白的细胞裂解物一起使用，无需纯化蛋白质、纯化合物和蛋白质固定化。通过用 Ni 离子修饰 UiO-66-NH 的表面来特异性捕获 His 标记的 SIRT1 而保持其酶活性，合成了高性能的 Ni@Tyr@UiO-66-NH。通过双重识别，其中 Ni@Tyr@UiO-66-NH 识别 SIRT1，而 SIRT1 识别其配体，从复杂基质中识别 SIRT1 抑制剂的过程大大简化。该方法允许从中草药中高效发现 16 种天然 SIRT1 抑制剂。其中，6 种化合物被充分表征，发现 suffruticosol A 的 IC 值为 0.95 ± 0.12 μM，非常出色。总的来说，本研究提出了一种创新的基于双重识别的策略，可有效地鉴定 SIRT1 抑制剂，为开发针对 CNS 疾病的药物提供了科学线索。
