非激动剂PPARγ连接体阻断Cdk5-介导酸化的抗糖尿病作用
Jang Hyun Choi1, Alexander S Banks, Theodore M Kamenecka
1Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|September 6, 2011
概括
针对PPARγ酸化的新型化合物提供了新的抗糖尿病药物. SR1664有效地治疗糖尿病,没有像体重增加这样的常见副作用,与传统的 thiazolidinediones 不同.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 内分泌学 在内分泌学.
背景情况:
- 过氧体增殖器激活受体玛 (PPARγ) 是抗糖尿病药物 thiazolidinedione (TZD) 的目标.
- TZDs是激动剂,但也阻断了与肥胖相关的Cdk5-介导的PPARγ酸化.
- 现有的PPARγ药物会引起诸如水分保留和体重增加等副作用.
研究的目的:
- 开发针对PPARγ酸化的新型合成化合物.
- 为了研究具有独特结合方式的化合物,缺乏经典的激进作用.
- 评估新化合物的抗糖尿病活性和副作用概况.
主要方法:
- 合成了具有独特PPARγ结合的新型化合物.
- 在培养脂肪细胞和抗胰岛素小鼠模型中评估化合物活性.
- 在体外对Cdk5介导的PPARγ酸化和骨形成的评估影响.
主要成果:
- 新型化合物阻断了Cdk5介导的PPARγ酸化,没有经典的激动作用.
- 化合物SR1664在体内表现出强大的抗糖尿病活性.
- SR1664并没有诱导液体保留,体重增加或影响培养中的骨形成.
结论:
- 针对Cdk5介导的PPARγ酸化为糖尿病提供了一种新的治疗策略.
- SR1664代表了一类潜在的新型抗糖尿病药物,具有改善的副作用概况.
- 选择性PPARγ调制可以克服当前TZD疗法的局限性.
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