Lipid bilayer position and orientation of novel carprofens, modulators of γ-secretase in Alzheimer's disease.

Abstract

γ-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-β peptides. Amyloid-β peptides are considered causative agents for Alzheimer's disease and drugs targeted at γ-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed γ-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to γ-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner.

• Authors: Evgeniy Salnikov, Binia Drung, Gabin Fabre, Anna Itkin, Michal Otyepka, Norbert A Dencher, Boris Schmidt, Thomas Hauß, Patrick Trouillas, Burkhard Bechinger
• Journal: Biochimica et biophysica acta. Biomembranes (Biochim Biophys Acta Biomembr) Vol. 1860 Issue 11 Pg. 2224-2233 (11 2018) ISSN: 1879-2642 [Electronic] Netherlands
• PMID: 30409518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Carbazoles
• Lipid Bilayers
• Amyloid Precursor Protein Secretases
• carprofen

Topics

• Alzheimer Disease (metabolism)
• Amyloid Precursor Protein Secretases (drug effects, metabolism)
• Carbazoles (metabolism, pharmacology)
• Humans
• Lipid Bilayers
• Magnetic Resonance Spectroscopy (methods)
• Molecular Dynamics Simulation