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Lipophilicity of the Cystic Fibrosis Drug, Ivacaftor (VX-770), and Its Destabilizing Effect on the Major CF-causing Mutation: F508del.
Chin, Stephanie; Hung, Maurita; Won, Amy; Wu, Yu-Sheng; Ahmadi, Saumel; Yang, Donghe; Elmallah, Salma; Toutah, Krimo; Hamilton, C Michael; Young, Robert N; Viirre, Russell D; Yip, Christopher M; Bear, Christine E.
Afiliação
  • Chin S; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Hung M; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Won A; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Wu YS; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Ahmadi S; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Yang D; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Elmallah S; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Toutah K; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Hamilton CM; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Young RN; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Viirre RD; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Yip CM; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
  • Bear CE; Department of Molecular Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (S.C., M.H., Y.-S.W., S.A., D.Y., C.E.B.); Departments of Biochemistry (S.C., C.E.B.) and Physiology (M.H., Y.-S.W., S.A., C.E.B.), and Institute of Biomaterials and Biomedical Engineering (A.W., C.M.Y.), Universi
Mol Pharmacol ; 94(2): 917-925, 2018 08.
Article em En | MEDLINE | ID: mdl-29903751
ABSTRACT
Deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cystic fibrosis (CF)-causing mutation. Recently, ORKAMBI, a combination therapy that includes a corrector of the processing defect of F508del-CFTR (lumacaftor or VX-809) and a potentiator of channel activity (ivacaftor or VX-770), was approved for CF patients homozygous for this mutation. However, clinical studies revealed that the effect of ORKAMBI on lung function is modest and it was proposed that this modest effect relates to a negative impact of VX-770 on the stability of F508del-CFTR. In the current studies, we showed that this negative effect of VX-770 at 10 µM correlated with its inhibitory effect on VX-809-mediated correction of the interface between the second membrane spanning domain and the first nucleotide binding domain bearing F508del. Interestingly, we found that VX-770 exerted a similar negative effect on the stability of other membrane localized solute carriers (SLC26A3, SLC26A9, and SLC6A14), suggesting that this negative effect is not specific for F508del-CFTR. We determined that the relative destabilizing effect of a panel of VX-770 derivatives on F508del-CFTR correlated with their predicted lipophilicity. Polarized total internal reflection fluorescence microscopy on a supported lipid bilayer model shows that VX-770, and not its less lipophilic derivative, increased the fluidity of and reorganized the membrane. In summary, our findings show that there is a potential for nonspecific effects of VX-770 on the lipid bilayer and suggest that this effect may account for its destabilizing effect on VX-809- rescued F508del-CFTR.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinolonas / Regulador de Condutância Transmembrana em Fibrose Cística / Fibrose Cística / Transportadores de Sulfato / Aminofenóis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Pharmacol Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinolonas / Regulador de Condutância Transmembrana em Fibrose Cística / Fibrose Cística / Transportadores de Sulfato / Aminofenóis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Pharmacol Ano de publicação: 2018 Tipo de documento: Article