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

@article{citeulike:2718353, abstract = {-Secretase plays a critical role in -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 -secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active -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 -secretase, this strategy could also be used in designing potent drugs against other membrane protein targets. 10.1126/science.1156609}, author = {Rajendran, Lawrence and Schneider, Anja and Schlechtingen, Georg and Weidlich, Sebastian and Ries, Jonas and Braxmeier, Tobias and Schwille, Petra and Schulz, Jorg B. and Schroeder, Cornelia and Simons, Mikael and Jennings, Gary and Knolker, Hans-Joachim and Simons, Kai}, citeulike-article-id = {2718353}, citeulike-linkout-0 = {http://dx.doi.org/10.1126/science.1156609}, citeulike-linkout-1 = {http://www.sciencemag.org/cgi/content/abstract/320/5875/520}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18436784}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18436784}, day = {25}, doi = {10.1126/science.1156609}, journal = {Science}, keywords = {alzheimer}, month = {April}, number = {5875}, pages = {520--523}, posted-at = {2008-04-25 13:48:58}, priority = {2}, title = {Efficient Inhibition of the Alzheimer's Disease {beta}-Secretase by Membrane Targeting}, url = {http://dx.doi.org/10.1126/science.1156609}, volume = {320}, year = {2008} }

TY - JOUR ID - citeulike:2718353 L3 - citeulike-article-id:2718353 N2 - -Secretase plays a critical role in -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 -secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active -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 -secretase, this strategy could also be used in designing potent drugs against other membrane protein targets. 10.1126/science.1156609 IS - 5875 JF - Science EP - 523 TI - Efficient Inhibition of the Alzheimer's Disease {beta}-Secretase by Membrane Targeting VL - 320 SP - 520 KW - alzheimer AU - Rajendran, Lawrence AU - Schneider, Anja AU - Schlechtingen, Georg AU - Weidlich, Sebastian AU - Ries, Jonas AU - Braxmeier, Tobias AU - Schwille, Petra AU - Schulz, Jorg AU - Schroeder, Cornelia AU - Simons, Mikael AU - Jennings, Gary AU - Knolker, Hans-Joachim AU - Simons, Kai PY - 2008/04/25/ UR - http://dx.doi.org/10.1126/science.1156609 ER -