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(c) 2002 BMO

"Single Molecule Analysis of Protein Aggregation and Prions by SIFT"
Hans A. Kretzschmar, Uwe Bertsch, Konstanze F. Winklhofer, Thomas Hirschberger, Jan Bieschke, Petra Weber, F. Ulrich Hartl, Paul Tavan, Jörg Tatzelt, and Armin Giese
J Neuropathol Exp Neurol 64 441 (2005)

Protein aggregation is a key event in a number of diseases such as Alzheimer`s disease, Parkinson`s disease and prion diseases. Dual-color scanning for intensely fluorescent targets (SIFT), which has been used in the diagnosis of prion diseases, is presented here as a general technique to quantify and charachterize protein aggregates. In the case of prion diseases the prion protein (PrPC), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted scrapie-isoform (PrPSc), which forms amyloid aggregates. This conversion depends on direct PrPC/PrPSc interaction. We have developed a high-throughput SIFT assay for the identification of drugs, which interfere with this interaction at the molecular level. Screening a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose-response curves. Among these, six compounds displayed an inhibitory effect on PrPSc propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N-benzylidene-benzohydrazide (NBB) core microstructure. Preliminary experiments with NBB in scrapie-infected mice have shown positive effects. Thus the combination of a high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new anti-prion drugs, which corroborates that interaction of PrPC and PrPSc is a crucial molecular step in the propagation of prions. In addition, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.

BMO authors (in alphabetic order):
Thomas Hirschberger
Paul Tavan

Assoziierte Projekte:
Molecular Modeling and Pattern Recognition for Computational Analysis and Support of Screening Experiments Aiming at the Development of Anti-TSE pharmaceuticals

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Letzte Änderung: 2016-09-14 13:34