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Journal of Virology, June 2005, p. 7785-7791, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7785-7791.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Systematic Identification of Antiprion Drugs by High-Throughput Screening Based on Scanning for Intensely Fluorescent Targets

Uwe Bertsch,1 Konstanze F. Winklhofer,2 Thomas Hirschberger,3 Jan Bieschke,1,{dagger} Petra Weber,1 F. Ulrich Hartl,2 Paul Tavan,3 Jörg Tatzelt,2 Hans A. Kretzschmar,1 and Armin Giese1*

Zentrum für Neuropathologie und Prionforschung, Ludwig Maximilians Universität, Feodor Lynen Str. 23, D-81377 München, Germany,1 Department of Cellular Biochemistry, Max Planck Institute for Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany,2 Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, Ludwig Maximilians Universität, Oettingenstr. 67, D-80538 München, Germany3

Received 23 November 2004/ Accepted 7 February 2005

Conformational changes and aggregation of specific proteins are hallmarks of a number of 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 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 of 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 an N'-benzylidene-benzohydrazide 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 antiprion drugs, which corroborates that interaction of PrPC and PrPSc is a crucial molecular step in the propagation of prions. Moreover, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.

* Corresponding author. Mailing address: Zentrum für Neuropathologie und Prionforschung, Ludwig Maximilians Universität, Feodor Lynen Str. 23, D-81377 München, Germany. Phone: 49 89 2180 78048. Fax: 49 89 2180 78037. E-mail: armin.giese{at}med.uni-muenchen.de.

{dagger} Present address: The Scripps Research Institute, 10550 N. Torrey Pines Rd., BCC 265, La Jolla, CA 92037.

Journal of Virology, June 2005, p. 7785-7791, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7785-7791.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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