Gao Jian, Chen Qing-Qing, Huang Ye, Li Kai-Hang, Geng Xiao-Ju, Wang Tao, Lin Qi-Si, Yao Ruo-Si
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Xuzhou Medical University Technology Transfer Center Co., Ltd., Xuzhou Medical University, Xuzhou, China.
Front Pharmacol. 2021 Apr 28;12:653233. doi: 10.3389/fphar.2021.653233. eCollection 2021.
Diabetic nephropathy (DN) is one of the most important medical complications in diabetic patients, which is an essential cause of end-stage renal disease in diabetic patients and still lacks effective medicines. Silent information regulator 1 (SIRT1) is closely related to the occurrence and development of DN. Activation of SIRT1 could significantly improve the symptoms of DN, while the activities of SIRT1 activators need to be further improved. Based on the crystal structure of SIRT1, structure and ligand-based approaches were carried out, and a lead compound 4,456-0661 (renamed as M1) was identified. Moreover, seven M1 analogues (6a-6g) were designed using a structure-based drug design strategy followed by bioactivity evaluation with SRTR2104 used as positive drugs. Among the target molecules, compounds M1, 6b, and 6d were proved to be potent SIRT1 activators, the activities of which are comparable to SRT2104. More importantly, compounds M1, 6b, and 6d could resist high glucose-induced apoptosis of HK-2 cells by activating SIRT1 and deacetylation of p53. Apart from the beneficial effect on apoptosis of DN, these compounds also alleviated high glucose stimulating inflammation response in HK-2 cells through SIRT1/NF-κB (p65) pathway. Consequently, M1, 6b, and 6d could be promising drug candidates for SIRT1 related diseases.
糖尿病肾病（DN）是糖尿病患者最重要的医学并发症之一，是糖尿病患者终末期肾病的重要病因，且仍缺乏有效的药物。沉默信息调节因子1（SIRT1）与DN的发生发展密切相关。激活SIRT1可显著改善DN症状，而SIRT1激活剂的活性有待进一步提高。基于SIRT1的晶体结构，采用基于结构和配体的方法，鉴定出一种先导化合物4,456 - 0661（重新命名为M1）。此外，采用基于结构的药物设计策略设计了7种M1类似物（6a - 6g），随后以SRTR2104作为阳性药物进行生物活性评价。在目标分子中，化合物M1、6b和6d被证明是有效的SIRT1激活剂，其活性与SRT2104相当。更重要的是，化合物M1、6b和6d可通过激活SIRT1和使p53去乙酰化来抵抗高糖诱导的HK - 2细胞凋亡。除了对DN细胞凋亡有有益作用外，这些化合物还通过SIRT1/NF -κB（p65）途径减轻了HK - 2细胞中的高糖刺激炎症反应。因此，M1、6b和6d可能是治疗SIRT1相关疾病的有前景的候选药物。
