Journal article

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Guido Veit, Ariel Roldan, Mark A Hancock, Dillon F Da Fonte, Haijin Xu, Maytham Hussein, Saul Frenkiel, Elias Matouk, Tony Velkov, Gergely L Lukacs

JCI Insight | AMER SOC CLINICAL INVESTIGATION INC | Published : 2020

Abstract

Based on its clinical benefits, Trikafta - the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) - was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator (CFTR) on at least 1 allele. Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) ..

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Grants

Awarded by Canadian Institutes of Health Research


Awarded by National Institute of Diabetes & Digestive & Kidney Diseases


Awarded by Canada Foundation for Innovation (CFI)


Funding Acknowledgements

This work was supported by the Canadian Institutes of Health Research (MOP-142221 to GLL and PJT-153095 to GV, EM, and GLL), National Institute of Diabetes & Digestive & Kidney Diseases (5R01DK075302 to GLL), the Cystic Fibrosis Foundation Therapeutics to GLL, and Cystic Fibrosis Canada to GLL. GLL is a Canada Research Chair. We acknowledge the Canada Foundation for Innovation (CFI) for infrastructure support: Bruker UltrafleXtreme MALDI-TOF/TOF system (grant no. 32616, awarded to Gerhard Multhaup and GLL) and BIACORE T200 SPR system (grant no. 228340 awarded to Gerhard Multhaup).