Efficient Inhibition of the Alzheimer's Disease β-Secretase by Membrane Targeting

• Published in: Science (American Association for the Advancement of Science) 2008-04, Vol.320 (5875), p.520-523
• Main Authors: Rajendran, Lawrence, Schneider, Anja, Schlechtingen, Georg, Weidlich, Sebastian, Ries, Jonas, Braxmeier, Tobias, Schwille, Petra, Schulz, Jörg B, Schroeder, Cornelia, Simons, Mikael, Jennings, Gary, Knölker, Hans-Joachim, Simons, Kai
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Animals, Genetically Modified; Biological and medical sciences; Cell membranes; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drosophila - genetics; Drug Delivery Systems; Drug Design; Endocytosis; Endosomes; Endosomes - enzymology; Enzymes; Focalism; HeLa Cells; Humans; Intracellular Membranes - metabolism; Medical sciences; Membrane Microdomains - enzymology; Mice; Neurology; Organic mental disorders. Neuropsychology; P branes; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rafts; Sterols
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1156609

β-Secretase plays a critical role in β-amyloid formation and thus provides a therapeutic target for Alzheimer's disease. Inhibitor design has usually focused on active-site binding, neglecting the subcellular localization of active enzyme. We have addressed this issue by synthesizing a membrane-anchored version of a β-secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active β-secretase found in endosomes and also reduced the dimensionality of the inhibitor, increasing its local membrane concentration. This inhibitor reduced enzyme activity much more efficiently than did the free inhibitor in cultured cells and in vivo. In addition to effectively targeting β-secretase, this strategy could also be used in designing potent drugs against other membrane protein targets.