Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstr. 30, 95447, Bayreuth, Germany.
Sapienza University Roma, Department of Drug Chemistry and Technologies and Pasteur Institute of the Cenci-Bolognetti Foundation, P. le A. Moro 5, 00185, Rome, Italy.
Angew Chem Int Ed Engl. 2017 Jan 19;56(4):1007-1011. doi: 10.1002/anie.201610082. Epub 2016 Dec 19.
Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.
Sirtuins 是调节代谢和应激反应的蛋白去酰基酶，与与衰老相关的疾病有关。人们正在寻找人类 Sirtuins Sirt1-7 的小分子激活剂作为化学工具和潜在的治疗药物，例如用于癌症。激活剂可用于 Sirt1 并利用其独特的 N 端，而缺乏用于 Sirt2-7 的类似药物的激活剂。我们合成并筛选了吡咯并[1,2-a]喹喔啉衍生物，得到了第一个合成的 Sirt6 激活剂。生化测定显示化合物直接与 Sirt6 催化核心结合，并且对肽底物的 Sirt6 依赖性去乙酰化作用以及完整核小体具有很强的激活作用。Sirt6/激活剂复合物的晶体结构表明，这些化合物结合到 Sirt6 特异性酰基通道口袋中，并确定了关键相互作用。我们的结果确立了小分子对 Sirt6 的有效激活，并为进一步开发 Sirt6 激活剂作为工具和治疗药物提供了结构基础。
