title: A genomic signature approach to rescue ΔF508-cystic fibrosis transmembrane conductance regulator biosynthesis and function.
abstract: The most common cystic fibrosis (CF) mutation, ΔF508, causes protein misfolding, leading to proteosomal degradation. We recently showed that expression of miR-138 enhances CF transmembrane conductance regulator (CFTR) biogenesis and partially rescues ΔF508-CFTR function in CF airway epithelia. We hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting ΔF508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore ΔF508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving ΔF508-CFTR trafficking, maturation, and chloride current. We identified four small molecules that partially restore ΔF508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving ΔF508-CFTR function. There are few CF therapies based on new molecular insights. Querying the Connectivity Map with relevant genomic signatures offers a method to identify new candidates for rescuing ΔF508-CFTR function.
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Shyam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Osterhaus
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D001712:Biperiden / Q000737:chemistry; D001980:Bronchi / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry; D019295:Computational Biology; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D023281:Genomics; D006367:HeLa Cells; D006801:Humans; D010641:Phenotype; D010918:Pizotyline / Q000737:chemistry; D021381:Protein Transport; D011729:Pyridostigmine Bromide / Q000737:chemistry; D020545:Respiratory Mucosa / Q000378:metabolism; D012984:Software; D014635:Valproic Acid / Q000737:chemistry
chemical_list: D002712:Chlorides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D010918:Pizotyline; D001712:Biperiden; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014635:Valproic Acid; D011729:Pyridostigmine Bromide
keywords: Connectivity Map; airway epithelia; corrector compound 18; cystic fibrosis; small molecule compound