Direct interaction of a CFTR potentiator and a CFTR corrector with phospholipid bilayers

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• 作者：Debora Baroni (1)
  Olga Zegarra-Moran (2)
  Agneta Svensson (3)
  Oscar Moran (1)
  
• 关键词：Small ; angle X ; ray scattering ; Bilayer ; Cystic fibrosis transmembrane conductance regulator (CFTR) ; Potentiator ; Corrector
• 刊名：European Biophysics Journal
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：43
• 期：6-7
• 页码：341-346
• 全文大小：
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• 作者单位：Debora Baroni (1)
  Olga Zegarra-Moran (2)
  Agneta Svensson (3)
  Oscar Moran (1)
  
  1. Istituto di Biofisica, CNR, via De Marini, 6, 16149, Genoa, Italy
  2. Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, via Gerolamo Gaslini, 5, 16148, Genoa, Italy
  3. Cells-Alba, Carretera, BP 1413, 08290, Cerdanyola del Vall猫s, Barcelona, Spain
  
• ISSN：1432-1017

文摘

Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors are new drugs that target the basic CFTR protein defect and are expected to benefit cystic fibrosis patients. To optimize the substances so far proposed for human use, and to minimise unwanted side effects, it is essential to investigate possible interactions between the drugs and cell components. We used small-angle X-ray scattering with synchrotron radiation to analyse the effects of two representative drugs, the potentiator VX-770 (Ivacaftor), approved for human use, and the corrector VX-809 (Lumacaftor), on a model phospholipid membrane. By reconstruction of the electron density profile of unilamellar vesicles treated with VX-770 or VX-809 we found that these drugs penetrate the phospholipid bilayer. VX-809 becomes homogeneously distributed throughout the bilayer whereas VX-770 accumulates predominantly in the internal leaflet, behaviour probably favoured by the asymmetry of the bilayer, because of vesicle curvature. Penetration of the bilayer by these drugs, probably as part of the mechanisms of permeation, causes destabilization of the membrane; this must be taken into account during future drug development.