Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Applied Science & Technology, University of California, Berkeley, CA 94720, USA.
Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Dec;1862(12):1606-1617. doi: 10.1016/j.bbalip.2017.09.004. Epub 2017 Sep 12.
Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD.
胆固醇酯转移蛋白 (CETP) 抑制剂是治疗血脂异常的一类新型治疗药物，可同时改善两种主要的心血管疾病 (CVD) 风险因素：升高的低密度脂蛋白 (LDL) 胆固醇和降低的高密度脂蛋白 (HDL) 胆固醇。然而，其疗效的详细分子机制以及该类药物之间的任何潜在机制差异仍知之甚少。在此，我们使用电子显微镜 (EM) 研究了三种此类药物（Torcetrapib、Dalcetrapib 和 Anacetrapib）对 CETP 结构、CETP-脂蛋白复合物形成和 CETP 介导的胆固醇酯 (CE) 转移的影响。我们发现，尽管这些抑制剂都没有改变 CETP 的结构或 CETP-脂蛋白二元复合物的构象，但所有抑制剂，特别是 Torcetrapib 和 Anacetrapib，都增加了二元复合物的结合比（例如，HDL-CETP 和 LDL-CETP），并降低了 HDL-CETP-LDL 三元复合物的结合比。更多二元复合物和更少三元复合物的发现反映了一种新的抑制机制：CETP 的一个远端与第一个脂蛋白结合会触发另一个远端的构象变化，从而导致与第二个脂蛋白的结合比降低，以及脂蛋白之间的 CE 转移率降低。因此，我们提出了一种新的抑制剂设计，应该降低二元和三元复合物的形成。二元复合物浓度的降低可能会阻止抑制剂在治疗 CVD 期间脂蛋白代谢中通过二元复合物的紧密结合被诱导进入细胞。
