文章摘要
噻唑衍生物WSF-SN-10激活AMPK的机制研究
The Mechanism of AMPK Activation by WSF-SN-10, a Thiazole Derivative
投稿时间:2019-03-01  修订日期:2019-03-01
DOI:
中文关键词: 噻唑衍生物  WSF-SN-10  AMPK  AMP/ATP  Ca2+
英文关键词: Thiazole derivatives  WSF-SN-10  AMPK  AMP/ATP  Ca2+
基金项目:国家自然科学基金项目(31570760、31470592)
作者单位E-mail
杨洋 清华大学生命科学学院 yyang16@mails.tsinghua.edu.cn 
王芸芸 南京林业大学化学工程系  
李小川 清华大学生命科学学院  
孙楠 南京林业大学化学工程系  
张志杰 中国中医科学院  
王石发 南京林业大学  
李珍 清华大学生命科学学院 lizhen@mail.tsinghua.edu.cn 
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中文摘要:
      目的:AMPK是治疗代谢紊乱的关键药物靶点。升高AMP/ATP比值或升高细胞内的Ca2+浓度为激活AMPK的主要途径。治疗II型糖尿病的一线药物双胍类和噻唑烷二酮类药物均为AMPK激活剂,但这两类药物均存在一定的副作用。本课题旨在噻唑衍生物中筛选新的AMPK激活剂并探究其激活AMPK的分子机制,以期找到副作用少的II型糖尿病治疗药物。方法:用14种噻唑衍生物处理293T细胞,用Western Blot筛选能显著提高AMPK磷酸化水平的化合物。用HPLC和FACS分别检测该化合物对细胞内AMP/ATP比值和Ca2+浓度的影响,探究其激活AMPK的分子机制。结果:WSF-SN-10(2-(2-(6,6-二甲基双环[3,1,1]庚-2-亚基)肼基)-4-(4-氰基苯基)噻唑)为14种噻唑衍生物中活性最强的AMPK激活剂;用WSF-SN-10处理293T细胞后,细胞内的AMP/ATP比值和LKB1的磷酸化水平显著增加,同时Ca2+浓度无明显变化,说明WSF-SN-10通过增加细胞内的AMP/ATP比值来激活AMPK。结论:噻唑衍生物WSF-SN-10能抑制细胞内的ATP合成来间接激活AMPK,是治疗II型糖尿病和肥胖症的潜在药物。
英文摘要:
      Objective: AMP-activated protein kinase (AMPK) is a prime therapeutic candidate for obesity-related metabolic disorders. It is activated (phosphorylated at Thr172) mainly by increasing the ratio of AMP/ATP and increasing intracellular Ca2+ concentration. Biguanides and Thiazolidinediones are first-line drugs used in the treatment of type II diabetes, and are both AMPK activators. However, they are associated with various undesirable side effects. In this study, we search among thiazole derivatives for the strongest AMPK activator and investigate its molecular mechanism of AMPK activation, to identify potent antidiabetic drugs with few side effects. Methods: 293T cells were treated with 14 thiazole derivatives and Western Blot was used to find out the strongest AMPK activator. HPLC and FACS were used respectively to measure intracellular ratio of AMP/ATP and intracellular Ca2+ concentration, to investigate its molecular mechanism of AMPK activation. Result: WSF-SN-10 was the strongest AMPK activator among the 14 thiazole derivatives; WSF-SN-10 increased the ratio of AMP/ATP and the level of LKB1 phosphorylation, but did not increase Ca2+ concentration in 293T cells. Therefore, WSF-SN-10 activates AMPK by increasing intracellular ratio of AMP/ATP. Conclusions: WSF-SN-10 is a novel AMPK activator which activates AMPK by inhibiting intracellular ATP synthesis, making it a potential drug candidate for the treatment of Type II diabetes and obesity.
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