NR AXND
AU Giese,A.; Wagner,J.; Bertsch,U.; Mitteregger,G.; Eiden,M.; Geissen,M.; Leidel,F.; Hirschberger,T.; Tavan,P.; Tatzelt,J.; Schmidt,B.; Groschup,M.H.; Kretzschmar,H.A.
TI Systematic Development of New Compounds for the Causal Therapy of Prion Diseases based on Molecular High-throughput Screening
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.17
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB We developed a high-throughput screening assay based on the SIFT (Scanning for Intensely Fluorescent Targets) technique for the identification of drugs, which interfere with the interaction between PrPc and PrPsc at the molecular level. Screening a library of 10,000 drug-like compounds yielded 80 active compounds, 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 shared a N'-benzylidenebenzohydrazide (NBB) core structure, which therefore represents a new lead structure for the development of therapeutics against prion diseases. Molecular SIFT screening of a second library of 10,000 drug-like compounds in combination with a systematic primary cell-culture screening of the same compound libraries, and molecular screening of newly generated focused compound libraries resulted in the identification of further potential lead structures with favourable medical chemistry profiles. Selected compounds including NBBs were also tested in vivo and could be shown to significantly prolong survival times of Scrapie-infected mice when applied i.p. for 14 days late in the incubation period.
AD A. Giese, J. Wagner, U. Bertsch, G. Mitteregger, H. Kretzschmar, Ludwig-Maximilians Universität München, Zentrum für Neuropathologie und Prionforschung, Germany; M. Eiden, M. Geissen, F. Leidel, M. Groschup, Friedrich-Löffler-Institut, Germany; T. Hirschberger, P. Tavan, Ludwig-Maximilians Universität München, Theoretische Biophysik, Germany; J. Tatzelt, Ludwig-Maximilians Universität München, Adolf-Butenandt-Institut, Germany; B. Schmidt, Technische Universität Darmstadt, Clemens-Schöpf-Institut, Germany
SP englisch
PO Schottland