title: Membrane anchored and lipid raft targeted β-secretase inhibitors for Alzheimer's disease therapy.
abstract: β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the β-secretase is present. In addition, membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.
authors: Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zürich, Zürich, Switzerland.
authors: Saoussen
authors: S
authors: Ben Halima
authors: Lawrence
authors: L
authors: Rajendran
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological
chemical_list: D004791:Enzyme Inhibitors; D006017:Glycolipids; D053829:Amyloid Precursor Protein Secretases