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

摘要

gamma-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-beta peptides. Amyloid-beta peptides are considered causative agents for Alzheimer's disease and drugs targeted at gamma-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed gamma-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 gamma-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.