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阐明DNA编码图书馆打击的非传统绑定模式为Sirtuin 6抑制剂的发展提供了蓝图

Weijie You^1,2, Alba L Montoya³, Srikanta Dana^3,4

¹Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, 95447, Bayreuth, Germany.

|June 28, 2024

概括

塞尔图因6 (Sirt6) 抑制剂2-Pr表现出独特的结合,为开发针对衰老和癌症的向疗法提供了新的策略. 这一发现为Sirt6调节器的药物化学带来了进展.

科学领域:

生物化学生物化学
药用化学医学化学
分子生物学分子生物学

背景情况:

锡尔图因6 (Sirt6) 是一种关键的NAD+依赖性脱酶,与衰老和癌症有关.
开发选择性Sirt6调节器对于治疗干预和生物研究至关重要.
现有的Sirt6调制器缺乏明显的化学支架.

研究的目的:

为了研究一种新型Sirt6抑制剂的抑制机制,2-Pr.
通过对2-Pr.的化学修饰来探索结构-活性关系.
通过共同晶体结构分析,阐明2-Pr与Sirt6的结合方式.

主要方法:

利用DNA编码的库来识别Sirt6抑制剂2-Pr.
进行生物化学测试以评估抑制活性和异型选择性.
确定了Sirt6/ADP-ribose/2-Pr复合物的共同晶体结构.

主要成果:

鉴定了2-Pr,一种具有新型化学结构的强效和异型选择性Sirtuin 6抑制剂.
共同晶体结构揭示了前所未有的结合模式,其中2-Pr占据了乙通道并延伸到乙-氨酸结合口袋.
评估了2-Pr的化学修饰,提供了对结构-活性关系的见解.

结论:

2-Pr的独特结合模式为设计下一代Sirt6抑制剂提供了一个新的结构基础.
这项研究为开发针对衰老相关疾病和癌症的有力和有选择性的Sirt6向治疗方法开辟了新的途径.
这些发现有助于更深入地了解Sirtuin 6的酶功能和调制.

关键词:

乙烯结合口袋中的一个.晶体结构晶体结构用DNA编码的化学图书馆脱酶是一种脱酶.通过Sirt6的抑制,Sirt6的抑制.

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