Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity

Abstract

Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 µM and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators.

Recent Strategic Advances in CFTR Drug Discovery: An Overview

“…Important to note, the validity of the proposed pipeline can be already assessed retrospectively, by evaluating the degree of consensus of the prediction and results obtained with the various techniques employed. In effect, already reported cases of this consensus are: computational predictions vs. SPR [52] or vs. cell-based assays [49], immunoprecipitation vs. overlay assays or vs. SPR [70], SPR vs. thermostability assays or vs. cell-based assays [48].…”

“…Among the computational models listed above, only a few have been used to better characterize the binding mode of known F508del-CFTR-rescuing drugs, to virtually screen libraries of molecules aimed at the identification of new putative F508del-CFTR-binding compounds or to design new CFTR-targeted drugs [48,49]. On the contrary, a huge amount of computational studies has been developed in the attempt of clarifying at a molecular level the mechanism of action of F508del-CFTR-ligands, using several NBDs RX data [23,[50][51][52] or the more recent cryo EM structures [53].…”

Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review)

“…As the concentration of intracellular chloride ion increases, Protein Kinase a (PKa) is activated, causing the channel to open (19). Similarly, the extracellular chloride concentration also regulates channel gating, and increased concentrations of extracellular chloride promote the opening of channels (20). Thus, CFTR facilitates two-way permeability of chloride ions (20).…”

“…Similarly, the extracellular chloride concentration also regulates channel gating, and increased concentrations of extracellular chloride promote the opening of channels ( 20 ). Thus, CFTR facilitates two-way permeability of chloride ions ( 20 ). Previous studies have suggested that, in addition to regulating chloride ion transport through epithelial cells, CFTR is involved in the regulation of various ion transporters, including epithelial sodium channels, chloride/bicarbonate exchangers, sodium/proton exchangers and water channels ( 20 – 22 ).…”

“…Thus, CFTR facilitates two-way permeability of chloride ions ( 20 ). Previous studies have suggested that, in addition to regulating chloride ion transport through epithelial cells, CFTR is involved in the regulation of various ion transporters, including epithelial sodium channels, chloride/bicarbonate exchangers, sodium/proton exchangers and water channels ( 20 – 22 ). Therefore, CFTR-dependent physiological processes have a key role in maintaining homeostasis of pH, ions and water levels in the fluids of secretory epithelium ( 21 ).…”