Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction
Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction
复制标题
DOI：
10.1016/j.chembiol.2013.06.004
复制
发表时间：
2013-07-25
影响因子：
--
通讯作者：
Amaral, Margarida D.
中科院分区：
文献类型：
--
作者：
Farinha, Carlos M.;King-Underwood, John;Amaral, Margarida D.
囊性纤维化主要由F508 del突变引起，其由于错误折叠而损害CFTR蛋白离开内质网。VX-809是一种拯救F508 del-CFTR定位的小分子，最近进入临床试验，但作用机制（MoA）未知。在此，我们评估VX-809与F508 del-CFTR的遗传回复突变体、其他校正剂和低温是否是加和的或协同的，以确定其MoA。我们在联合治疗中探索并整合了这些不同的药物，展示了它们如何相互添加以在F508 del-CFTR纠正后识别其互补的MoA。我们的实验和建模数据虽然与VX-809与NBD 1：ICL 4界面的推定结合相容，但也表明其他化合物在不同构象位点/细胞检查点处进一步协同F508 del-CFTR校正的范围，因此表明需要联合疗法来完全拯救F508 del-CFTR。
Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. We explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR. Our experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR.