Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.

氯离子通道 CFTR 的活性受损是囊性纤维化的原因。14-3-3 蛋白已被证明可以稳定 CFTR 并增加其生物发生和活性。在这里，我们报告了稳定 14-3-3/CFTR 复合物的大环化合物的鉴定和作用机制。该分子可挽救 F508del-CFTR 的质膜定位和氯化物转运，并与 CFTR 药理学伴侣校正剂 lumacaftor (VX-809) 和三重组合 Trikafta® 共同作用。这种大环是研究 CFTR/14-3-3 相互作用和分子胶在囊性纤维化治疗中的潜力的有用工具。