Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Structure-guided combination therapy to potently improve the function of mutant CFTRs

Veit, Guido and Dreano, Elise and Avramescu, Radu and Bagdany, Miklos and Beitel, Lenore and Roldan, Ariel and Hancock, Mark and Lay, Cecilia and Li, Wei and Morin, Katie and Gao, Sandra and Puiying, Mak and Ainscow, Edward and Orth, Anthony and McNamara, Peter and Edelman, Aleksander and Frenkiel, Saul and Matouk, Elias and Sermet-Gaudelus, Isabelle and Barnes, William and Lukacs, Gergely (2018) Structure-guided combination therapy to potently improve the function of mutant CFTRs. Nature Medicine.

Abstract

Available drugs are unable to effectively rescue the folding defects in vitro and ameliorate the clinical-phenotype of cystic fibrosis (CF), caused by deletion of F508 (ΔF508 or F508del) and some point mutations in the CF transmembrane conductance regulator (CFTR), a plasma membrane (PM) anion channel. To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutants expression and function at the PM. High throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at the nucleotide binding domain (NBD1), NBD2 and their membrane spanning domains (MSDs) interfaces. While individually these compounds marginally improve ΔF508-CFTR folding efficiency, function, and stability, their combinations lead to ~50-100% of wild type-level correction in immortalized and primary human airway epithelia, and in mouse nasal epithelia. Likewise, corrector combinations were effective for rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.

Item Type: Article
Date Deposited: 30 Oct 2018 00:45
Last Modified: 30 Oct 2018 00:45
URI: https://oak.novartis.com/id/eprint/37480

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.