Efficient Inhibition of the Alzheimer's Disease β-Secretase by Membrane Targeting
Lawrence Rajendran,1
Anja Schneider,2
Georg Schlechtingen,3,4
Sebastian Weidlich,4
Jonas Ries,5
Tobias Braxmeier,3,4
Petra Schwille,5
Jörg B. Schulz,6
Cornelia Schroeder,4
Mikael Simons,2
Gary Jennings,3
Hans-Joachim Knölker,3,4
Kai Simons1*
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.
1 Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
2 Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
3 JADO Technologies GmbH, Tatzberg 47-51, 01307 Dresden, Germany.
4 Department of Chemistry, Technical University of Dresden, Bergstr. 66, 01069 Dresden, Germany.
5 Biotec, Biotechnologisches Zentrum, Tatzberg 47/49, 01307 Dresden, Germany.
6 Center of Neurological Medicine, Waldweg 33, 37073 Göttingen, Germany.
* To whom correspondence should be addressed. E-mail: simons{at}mpi-cbg.de
