Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Lawrence Rajendran - (Autor:in)
  • Anja Schneider - (Autor:in)
  • Georg Schlechtingen - , Technische Universität Dresden (Autor:in)
  • Sebastian Weidlich - , Technische Universität Dresden (Autor:in)
  • Jonas Ries - , Technische Universität Dresden (Autor:in)
  • Tobias Braxmeier - , Technische Universität Dresden (Autor:in)
  • Petra Schwille - , Technische Universität Dresden (Autor:in)
  • Jörg B. Schulz - , Universitätsmedizin Göttingen (Autor:in)
  • Cornelia Schroeder - , Technische Universität Dresden (Autor:in)
  • Mikael Simons - (Autor:in)
  • Gary Jennings - (Autor:in)
  • Hans Joachim Knölker - , Professur für Organische Chemie (II) (OC2) (Autor:in)
  • Kai Simons - (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)520-523
Seitenumfang4
FachzeitschriftScience
Jahrgang320
Ausgabenummer5875
PublikationsstatusVeröffentlicht - 25 Apr. 2008
Peer-Review-StatusJa

Externe IDs

PubMed 18436784

Schlagworte

ASJC Scopus Sachgebiete