Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting.
beta-Secretase plays a critical role in beta-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 beta-secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active beta-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 beta-secretase, this strategy could also be used in designing potent drugs against other membrane protein targets.
Rajendran
Lawrence
L
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
Schneider
Anja
A
Schlechtingen
Georg
G
Weidlich
Sebastian
S
Ries
Jonas
J
Braxmeier
Tobias
T
Schwille
Petra
P
Schulz
Jörg B
JB
Schroeder
Cornelia
C
Simons
Mikael
M
Jennings
Gary
G
Knölker
Hans-Joachim
HJ
Simons
Kai
K
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D021962:Membrane Microdomains / Q000201:enzymology; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013261:Sterols
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011480:Protease Inhibitors; D013261:Sterols; D053829:Amyloid Precursor Protein Secretases