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"Systematic identification of anti-prion drugs by high-throughput screening based on scanning for intensely fluorescent targets" Uwe Bertsch, Konstanze F. Winklhofer, Thomas Hirschberger, Jan Bieschke, Petra Weber, F. Ulrich Hartl, Paul Tavan, Jörg Tatzelt, Hans A. Kretzschmar, and Armin GieseJ. Virol. 79 7785-7791 (2005) Abstract: Conformational changes and aggregation of specific proteins are hallmarks of a number of neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease and prion diseases. In the case of prion diseases the prion protein (PrP), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted, so called, scrapie-isoform (PrPSc), which forms amyloid aggregates. This conversion, which is crucial for disease progression, depends on direct PrPC/PrPSc interaction. We developed a high-throughput assay based on Scanning for Intensely Fluorescent Targets (SIFT) 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 with half-maximal inhibitory effects ranging from 0.3 to 60 µM. Among these, six compounds displayed an inhibitory effect on PrPSc propagation in scrapie-infected N2a cells. Four of these candidate drugs share a N?-benzylidene-benzohydrazide (NBB) core structure. Thus the combination of high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new anti-prion drugs. Moreover, 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 |