Peptides and Pseudopeptides as SIRT6 Deacetylation Inhibitors

SIRT6 belongs to the family of histone deacetylases (class III), but it also has mono-ADP-ribosyltransferase activity. SIRT6 is a nuclear sirtuin that has been associated with aging, cellular protection, and sugar metabolism. Despite these important roles for SIRT6, thus far, there are only a few weak SIRT6 inhibitors available, and no structure–activity relationship (SAR) studies have been published. This is the first study concerning peptides and pseudopeptides as SIRT6 deacetylation inhibitors and the first SAR data concerning SIRT6. We also investigated the molecular interactions using a homology model. We report three compounds exhibiting 62–91% SIRT6 inhibition at 200 μM concentration. These compounds can serve as starting points for systematic SAR studies and SIRT6 inhibitor design.SIRT6隶属于III类组蛋白去乙酰化酶家族，同时兼具单ADP核糖基转移酶活性。SIRT6是一类核沉默蛋白（sirtuin），与衰老进程、细胞保护及糖代谢均存在密切关联。尽管SIRT6发挥着诸多关键生理功能，但截至目前仅能获取少数活性较弱的SIRT6抑制剂，且尚未有针对该靶点的构效关系（structure–activity relationship, SAR）研究公开发表。本研究首次以肽类与假肽类化合物作为SIRT6去乙酰化抑制剂展开探索，并首次公布了SIRT6相关的构效关系数据。研究期间，我们借助同源建模方法对相关分子相互作用进行了分析。本次研究共报道了3种在200 μM浓度下对SIRT6的抑制率可达62%~91%的化合物，上述化合物可作为系统性构效关系研究及SIRT6抑制剂开发的先导化合物。