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

E. Salnikov, B. Drung, G. Fabre, A. Itkin, M. Otyepka, NA. Dencher, B. Schmidt, T. Hauß, P. Trouillas, B. Bechinger,

. 2018 ; 1860 (11) : 2224-2233. [pub] 20180907

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19028102

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.

Citace poskytuje Crossref.org

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$a Salnikov, Evgeniy $u CNRS UMR 7177, Institut de Chimie, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France.
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$a Lipid bilayer position and orientation of novel carprofens, modulators of γ-secretase in Alzheimer's disease / $c E. Salnikov, B. Drung, G. Fabre, A. Itkin, M. Otyepka, NA. Dencher, B. Schmidt, T. Hauß, P. Trouillas, B. Bechinger,
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$a 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.
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$a Drung, Binia $u CSI Organic Chemistry and Biochemistry, Technische Universität Darmstadt, D-64287 Darmstadt, Germany.
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$a Fabre, Gabin $u LCSN EA1069, Faculty of Pharmacy, Université de Limoges, 2 rue de Dr. Marcland, 87025 Limoges Cedex, France.
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$a Itkin, Anna $u CNRS UMR 7177, Institut de Chimie, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France.
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$a Otyepka, Michal $u Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17 listopadu 12, 771 46 Olomouc, Czech Republic.
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$a Dencher, Norbert A $u CSI Organic Chemistry and Biochemistry, Technische Universität Darmstadt, D-64287 Darmstadt, Germany; Research Center for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.
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$a Schmidt, Boris $u CSI Organic Chemistry and Biochemistry, Technische Universität Darmstadt, D-64287 Darmstadt, Germany.
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$a Hauß, Thomas $u Macromolecular Crystallography, Helmholtz-Zentrum Berlin für Materialien und Energie, Albert-Einstein-Str. 15, D-12489 Berlin, Germany. Electronic address: hauss@helmholtz-berlin.de.
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$a Trouillas, Patrick $u Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17 listopadu 12, 771 46 Olomouc, Czech Republic; INSERM U1248, Faculty of Pharmacy, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France. Electronic address: patrick.trouillas@unilim.fr.
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$a Bechinger, Burkhard $u CNRS UMR 7177, Institut de Chimie, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France. Electronic address: bechinge@unistra.fr.
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