State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian 361005, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian 361005, China.
Biochim Biophys Acta Gen Subj. 2018 Oct;1862(10):2261-2270. doi: 10.1016/j.bbagen.2018.07.022. Epub 2018 Jul 23.
The 1,4-dihydropyridines (DHPs) are one of the most frequently prescribed classes of antihypertensive monotherapeutic agents worldwide. In addition to treating hypertension, DHPs also exert other beneficial effects, including hepatoprotective effects. However, the mechanism underlying the hepatoprotection remains unclear.
Biochemical AlphaScreen and cell-based reporter assays were employed to detect the activities of DHPs towards FXR. A crystallographic analysis was adopted to study the binding modes of four DHPs in complex with FXR. Acetaminophen (APAP)-treated wild-type and FXR knockout mice were used to investigate the functional dependence of the effects of the selected DHPs on FXR.
A series of DHPs were uncovered as FXR ligands with different activities for FXR, suggesting FXR might serve as an alternative drug target for DHPs. The structural analysis illustrated the specific three-blade propeller binding modes of four DHPs to FXR and explained the detailed mechanisms by which DHPs bind to and are recognized by FXR. The results in mice demonstrated that cilnidipine protected the liver from APAP-induced injury in an FXR-dependent manner.
This study reports the crystal structures of FXR in complex with four DHPs, and confirms that DHPs exert hepatoprotection by targeting FXR.
Our research not only reveals valuable insight for the design and development of next-generation Ca blocker drugs to provide safer and more effective treatments for cardiovascular disorders but also provides a novel and safe structural template for the development of drugs targeting FXR. Moreover, DHPs might be potentially repurposed to treat FXR-mediated diseases other than hypertension.
1,4-二氢吡啶类（DHPs）是全球范围内最常被处方的降压单药治疗药物之一。除了治疗高血压外，DHPs 还具有其他有益作用，包括肝保护作用。然而，其肝保护作用的机制尚不清楚。
采用生化 AlphaScreen 和基于细胞的报告基因检测法检测 DHPs 对 FXR 的活性。采用晶体学分析研究了 4 种 DHP 与 FXR 结合的结合模式。采用乙酰氨基酚（APAP）处理野生型和 FXR 敲除小鼠，研究所选 DHP 对 FXR 的作用的功能依赖性。
发现一系列具有不同 FXR 活性的 DHP 是 FXR 的配体，提示 FXR 可能成为 DHP 的替代药物靶点。结构分析说明了 4 种 DHP 与 FXR 的特定三叶桨式三叶螺旋桨结合模式，并解释了 DHP 与 FXR 结合和被识别的详细机制。小鼠的研究结果表明，西尼地平以 FXR 依赖的方式保护肝脏免受 APAP 诱导的损伤。
本研究报告了 FXR 与 4 种 DHP 复合物的晶体结构，并证实 DHP 通过靶向 FXR 发挥肝保护作用。
我们的研究不仅为设计和开发新一代 Ca 阻滞剂药物提供了有价值的见解，为心血管疾病提供更安全、更有效的治疗方法，而且为开发靶向 FXR 的药物提供了一种新颖、安全的结构模板。此外，DHPs 可能被重新用于治疗除高血压以外的 FXR 介导的疾病。
