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Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ?F508 cystic fibrosis transmembrane conductance regulator protein.

ABSTRACT: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ?F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ?F508-CFTR targeting) and potentiator ("Po", normalizing ?F508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ? force-field lowest energy assessment ? geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct ?-stacking conformations to elicit corrector and potentiator activities.

SUBMITTER: Knapp JM

PROVIDER: S-EPMC3277286 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ΔF508 cystic fibrosis transmembrane conductance regulator protein.

Knapp John M JM Wood Alex B AB Phuan Puay-Wah PW Lodewyk Michael W MW Tantillo Dean J DJ Verkman A S AS Kurth Mark J MJ

Journal of medicinal chemistry 20120123 3

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and c ...[more]

PMID: 22214395

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Project description:Background: Most cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to protein misfolding and degradation by the ubiquitin–proteasome system. Previous studies demonstrated that PIAS4 facilitates the modification of wild-type (WT) and F508del CFTR by small ubiquitin-like modifier (SUMO)-1, enhancing CFTR biogenesis by slowing immature CFTR degradation and producing increased immature CFTR band B. Methods: We evaluated two correction strategies using misfolding mutants, including the common variant, F508del. We examined the effects on mutant expression of co-expression with PIAS4 (E3 SUMO ligase), and/or the corrector, C18. To study the impact of these correction conditions, we transfected CFBE410- cells, a bronchial epithelial cell line, with a CFTR mutant plus: (1) empty vector, (2) empty vector plus overnight 5 μM C18, (3) PIAS4, and (4) PIAS4 plus C18. We assessed expression at steady state by immunoblot of CFTR band B, and if present, band C, and the corresponding C:B band ratio. The large PIAS4-induced increase in band B expression allowed us to ask whether C18 could act on the now abundant immature protein to enhance correction above the control level, as reported by the C:B ratio. Results: The data fell into three mutant CFTR categories as follows: (1) intransigent: no observable band C under any condition (i.e., C:B = 0); (2) throughput responsive: a C:B ratio less than control, but suggesting that the increased band C resulted from PIAS4-induced increases in band B production; and (3) folding responsive: a C:B ratio greater than control, reflecting C18-induced folding greater than that expected from increased throughput due to the PIAS4-induced band B level. Conclusion: These results suggest that the immature forms of CFTR folding intermediates occupy different loci within the energetic/kinetic folding landscape of CFTR. The evaluation of their properties could assist in the development of correctors that can target the more difficult-to-fold mutant conformations that occupy different sites within the CFTR folding pathway.

Dataset Information

Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ?F508 cystic fibrosis transmembrane conductance regulator protein.

Publications

Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ΔF508 cystic fibrosis transmembrane conductance regulator protein.

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