Membrane Anchored and Lipid Raft Targeted β-Secretase Inhibitors for Alzheimer's Disease Therapy

beta-secretase, a key enzyme involved in amyloid-beta generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of beta-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active beta-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of beta-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active beta-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the beta-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 beta-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.