近日，美国洛克菲勒大学Jue Chen及其研究团队的最新研究表明，分子结构显示Trikafta调节剂对Δ508 CFTR的协同挽救作用。相关论文于2022年10月21日发表在《科学》杂志上。

研究人员表示，引起囊性纤维化的主要突变是囊性纤维化跨膜传导调节器（CFTR）中苯丙氨酸508（Δ508）的缺失，导致CFTR生物生成和功能的严重缺陷。先进的疗法Trikafta结合了折叠校正剂tezacaftor（VX-661）、通道增效剂ivacaftor（VX-770）和双功能调节剂elexacaftor（VX-445）。然而，目前还不清楚elexacaftor是如何发挥其作用的，部分原因是Δ508 CFTR的结构尚不清楚。

研究人员展示了Δ508 CFTR在有无CFTR调节剂时的冷冻电镜结构。当单独使用时，elexacaftor部分纠正了Δ508 CFTR的域间组装缺陷，但当与I型校正剂结合使用时，则完全纠正了这种缺陷。这些数据说明了Trikafta中不同的调节剂如何协同挽救Δ508 CFTR的结构和功能。

附：英文原文

Title: Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators

Author: Karol Fiedorczuk, Jue Chen

Issue&Volume: 2022-10-21

Abstract: The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo–electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.

DOI: ade2216

Source: https://www.science.org/doi/10.1126/science.ade2216