Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry

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 t...

Full description

Saved in:

Bibliographic Details
Published in:	Chembiochem : a European journal of chemical biology Vol. 16; no. 14; pp. 2017 - 2022
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	Germany Blackwell Publishing Ltd 21-09-2015 Wiley Subscription Services, Inc
Subjects:	Aminopyridines - chemical synthesis Aminopyridines - chemistry Aminopyridines - pharmacology Benzodioxoles - chemical synthesis Benzodioxoles - chemistry Benzodioxoles - pharmacology CFTR correctors Click Chemistry Cystic fibrosis Cystic Fibrosis - drug therapy Cystic Fibrosis - genetics Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Drug Discovery Genes HEK293 Cells Humans Mutation Protein Binding protein expression VX-809 VX-809 click chemistry CFTR correctors protein expression cystic fibrosis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 CuI‐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. Click chemistry at work: We have designed and synthesized two VX‐809 derivatives, ALK‐809 and SUL‐809, that possess an alkyne functional group and retain the capacity of VX‐809 in rescuing F508del‐CFTR. We used CuI‐catalyzed click chemistry to demonstrate that these VX‐809 derivatives bind CFTR directly in order to exert their rescue capability.
Bibliography:	National Institutes of Health - No. R01-DK080834; No. R01-DK093045; No. R01L123535 istex:4CF36102948207827E2B3F414FD50C2525CA1FB1 ArticleID:CBIC201500123 ark:/67375/WNG-789GQB1S-P These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1439-4227 1439-7633
DOI:	10.1002/cbic.201500123