SIRT1是一种重要的蛋白去乙酰化酶，促进SIRT1酶活可以延缓衰老、预防与年龄老化相关疾病的发生，发展SIRT1激动剂药物成为研究机构和制药公司所追求的目标。但多年来在激动剂设计方面尚无进展，主要是因为不清楚为何化合物对SIRT1酶活的促进作用具有底物选择性。我们曾发现二芳基酰腙类化合物对SIRT1酶活的促进作用也具有底物选择性，通过解析它与SIRT1的复合物晶体结构，我们发现在SIRT1上存在主要和次要两个变构位点，主要变构位点对于化合物能否促进SIRT1酶活起关键作用。如果主要变构位点能同时容纳化合物和乙酰化底物残基侧链，化合物对该底物的去乙酰化则有促进作用。本课题基于复合物结构，结合分子模拟、虚拟筛选和化学合成方法，发展能促进其生理底物去乙酰化的真正SIRT1激动剂，它可作为小分子探针、有助于在生命不同层面揭示SIRT1的调控机制，也可为以SIRT1为靶标的新药研发提供先导化合物。

SIRT1 is an important protein deacetylase. Promoting SIRT1 activity may delay aging and prevent the age-related diseases. Naturally, development of SIRT1 activators has become the goal pursued by research institutes and pharmaceutical companies. However, there is no progress in development of SIRT1 activators over the years, mainly because it is unclear why the promotion of SIRT1 activity is substrate-dependent. Previously, we found that diarylhydrazone compounds promote the enzymatic activity of SIRT1 but the effect is substrate-dependent. Recently, we solved the crystal structure of SIRT1 in complex with the compound, and found that there are primary and secondary allosteric sites in SIRT1. The primary allosteric site plays a key role in promotion of SIRT1 activity. If the primary allosteric site accommodates both compound and the side chain of the acetylated substrate, the compound can promote the deacetylation of the substrate. Combined with molecular modeling, virtual screening, and chemical synthesis, and based on the crystal structures, this project aims to develop true SIRT1 activators that can promote the deacetylation of SIRT1 physiological substrates. The activators may serve as small molecule probes that help uncover the regulatory mechanisms of SIRT1 in various life processes, and also act as lead compounds for development of innovative drugs targeting SIRT1.