Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Details

OriginalspracheEnglisch
Seiten (von - bis)S25-S32
Seitenumfang8
FachzeitschriftJournal of Cystic Fibrosis
Jahrgang19
PublikationsstatusVeröffentlicht - 3 Jan. 2020
Peer-Review-StatusJa

Externe IDs

Scopus 85077308270
ORCID /0000-0003-2125-4045/work/141545221
ORCID /0000-0002-6209-2364/work/142237617

Schlagworte

Schlagwörter

  • CFTR Cl- channel, F508del-CFTR, Rare CF mutations, Protein folding, CFTR correction, CFTR potentiation, TRANSMEMBRANE CONDUCTANCE REGULATOR, SMALL-MOLECULE CORRECTORS, TEZACAFTOR-IVACAFTOR, GATING BEHAVIOR, CELL FUNCTION, IN-VITRO, PROTEIN, DELTA-F508, MUTATIONS, RESCUE