A Genomic Signature Approach to Rescue Delta F508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

作者：Ramachandran Shyam; Osterhaus Samantha R; Karp Philip H; Welsh Michael J; McCray Paul B Jr^*

来源：American Journal of Respiratory Cell and Molecular Biology, 2014, 51(3): 354-362.

DOI：10.1165/rcmb.2014-0007OC10

• cystic fibrosis
• small molecule compound
• Connectivity Map
• airway epithelia
• corrector compound 18

The most common cystic fibrosis (CF) mutation, Delta F508, 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 Delta F508-CFTR function in CF airway epithelia. We hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting Delta F508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore Delta F508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving Delta F508-CFTR trafficking, maturation, and chloride current. We identified four small molecules that partially restore Delta F508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving Delta F508-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 Delta F508-CFTR function.

• 出版日期2014-9