Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5
Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5
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DOI：
10.3390/molecules25122755
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发表时间：
2020-06-01
期刊：
影响因子：
4.6
通讯作者：
Liu, Dongxiang
中科院分区：
文献类型：
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作者：
Han, Haozhen;Li, Chunpu;Liu, Dongxiang
Sirtuins（SIRT 1 -7）是NAD（+）依赖性脱乙酰酶家族。它们调节许多生理过程，并在炎症、糖尿病、癌症和神经退行性疾病中发挥重要作用。沉默调节蛋白抑制剂在神经退行性疾病和各种癌症的治疗中具有潜在的应用。在此，我们鉴定了基于8-巯基-3，7-二氢-1H-嘌呤-2，6-二酮骨架的新的sirtuin抑制剂。为了阐明SIRT 3的抑制机制，通过分子对接建立了SIRT 3中抑制剂的结合模式，表明抑制剂占据乙酰赖氨酸结合位点，主要通过疏水相互作用与SIRT 3相互作用。通过SIRT 3的定点突变和抑制剂的构效关系分析验证了相互作用。酶动力学和微量热电泳结果表明，这些化合物对乙酰底物是竞争性抑制剂，对NAD（+）是混合型抑制剂。此外，我们证明了这些化合物是有效的SIRT 1/2/3/5泛抑制剂。这项研究为开发更有效的sirtuin抑制剂提供了新的命中。
Sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD(+). Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.