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Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry
Author(s) -
Sinha Chandrima,
Zhang Weiqiang,
Moon Chang Suk,
Actis Marcelo,
Yarlagadda Sunitha,
Arora Kavisha,
Woodroofe Koryse,
Clancy John P.,
Lin Songbai,
Ziady Assem G.,
Frizzell Raymond,
Fujii Naoaki,
Naren Anjaparavanda P.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500123
Subject(s) - cystic fibrosis transmembrane conductance regulator , mechanism of action , cystic fibrosis , mutation , chemistry , ivacaftor , potentiator , transmembrane protein , in vitro , regulator , gene , microbiology and biotechnology , biochemistry , biology , pharmacology , genetics , receptor
Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX‐809 has been reported to facilitate the folding and trafficking of F508del‐CFTR and augment its channel function. The mechanism of action of VX‐809 has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX‐809: does it bind CFTR directly in order to exert its action? We synthesized two VX‐809 derivatives, ALK‐809 and SUL‐809, that possess an alkyne group and retain the rescue capacity of VX‐809. By using Cu I ‐catalyzed click chemistry, we provide evidence that the VX‐809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to the elucidation of the mechanism of action of CFTR correctors and the design of more potent therapeutics to combat CF.