靶向线粒体Sirtuins蛋白的调控分子的发现、优化及生物活性评价

存在于线粒体中的三种Sirtuin蛋白（Sirt3、Sirt4和Sirt5）在调控细胞代谢的蛋白酰化以及ADP-核糖转移作用中扮演了重要角色，目前已逐渐成为药物研究的新型作用靶点。在前期研究中，我们利用所制备和收集的类天然杂环化合物库，基于Thermalshiftassay、Dose-dependent、PDI-selectivity以及FRET-based assay通过四轮筛选，发现了8个具有明显特异性亲和Sirt5蛋白作用的先导化合物。本项目拟发展多环噁二唑类及多环吲哚类杂环构建方法学，并开展对Sirt3和Sirt4蛋白的特异性亲和化合物的筛选。对获得的先导化合物，用基于片段的分子设计方法和类药性早期评价，对其进行结构优化，并进行肿瘤细胞抑制评价和基于蛋白印迹法的生物作用机制研究。以期获得结构新颖、机制明确的Sirtuin蛋白调控分子。

Sirtuins are key factors in the regulation of cell metabolism. Three Sirtuin subtypes (Sirt3, Sirt4 and Sirt5) which are found in mitochondria play important roles in the regulation of cellular protein acylation and ADP-ribose transfer. Its activation or inhibition are directly related to the occurrence and treatment of a variety of disease, and have gradually become the targets of drug research. In the previous study, we screened more than 3,000 heterocyclic compounds which were prepared and collected in our group, based on thermal shift assay, dose-dependent, PDI-selectivity, and FRET-based assay. Eight leading compounds were found and identified with distinctly specific affinity on the Sirt5 protein. On this project, we will develop heterocyclic synthesis methodologies for constructiing polycyclic oxadiazoles and polycyclic indoles, and carry out compounds screening on Sirt3 and Sirt4 protein specific affinity. Then, the lead compounds will be optimized using fragment-based molecular desing method and drug-lik evaluation. Meanwhile, the evaluation of anti-tumor cells will be carried out and th biological mechanism based on the method of protein blot will be studied.