Structure-guided combination therapy to potently improve the function of mutant CFTRs.
Guido VeitHaijin XuElise DreanoRadu G AvramescuMiklos BagdanyLenore K BeitelAriel RoldanMark A HancockCecilia LayWei LiKatelin MorinSandra GaoPuiying A MakEdward AinscowAnthony P OrthPeter McNamaraAleksander EdelmanSaul FrenkielElias MatoukIsabelle Sermet-GaudelusWilliam G BarnesGergely L LukacsPublished in: Nature medicine (2018)
Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although 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 against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.
Keyphrases
- cystic fibrosis
- wild type
- pseudomonas aeruginosa
- high throughput
- combination therapy
- lung function
- small molecule
- air pollution
- particulate matter
- single cell
- endothelial cells
- single molecule
- poor prognosis
- heavy metals
- polycyclic aromatic hydrocarbons
- stem cells
- transcription factor
- genome wide
- molecular dynamics simulations
- cancer therapy
- binding protein
- intellectual disability
- long non coding rna
- dna methylation
- mesenchymal stem cells
- protein protein
- chronic obstructive pulmonary disease
- dna binding