title: Piperazine derivatives inhibit PrP/PrP(res) propagation in vitro and in vivo.
abstract: Prion diseases are fatal neurodegenerative disorders, which are not curable and no effective treatment exists so far. The major neuropathological change in diseased brains is the conversion of the normal cellular form of the prion protein PrPc(C) into a disease-associated isoform PrP(Sc). PrP(Sc) accumulates into multimeres and fibrillar aggregates, which leads to the formation of amyloid plaques. Increasing evidence indicates a fundamental role of PrP(Sc) species and its aggregation in the pathogenesis of prion diseases, which initiates the pathological cascade and leads to neurodegeneration accompanied by spongiform changes. In search of compounds that have the potential to interfere with PrP(Sc) formation and propagation, we used a cell based assay for the screening of potential aggregation inhibitors. The assay deals with a permanently prion infected cell line that was adapted for a high-throughput screening of a compound library composed of 10,000 compounds (DIVERset 2, ChemBridge). We could detect six different classes of highly potent inhibitors of PrP(Sc) propagation in vitro and identified piperazine derivatives as a new inhibitory lead structure, which increased incubation time of scrapie infected mice.
authors: Institute of Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.
authors: Fabienne
authors: F
authors: Leidel
authors: Institute of Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.
authors: Martin
authors: M
authors: Eiden
authors: Department of Vascular Medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors: Markus
authors: M
authors: Geissen
authors: Theoretische Biophysik, Lehrstuhl für Biomolekulare Optik, Ludwig-Maximilians Universität, München, Germany.
authors: Thomas
authors: T
authors: Hirschberger
authors: Theoretische Biophysik, Lehrstuhl für Biomolekulare Optik, Ludwig-Maximilians Universität, München, Germany.
authors: Paul
authors: P
authors: Tavan
authors: Institut für Neuropathologie, Ludwig-Maximilians Universität, München, Germany.
authors: Armin
authors: A
authors: Giese
authors: Institut für Neuropathologie, Ludwig-Maximilians Universität, München, Germany.
authors: Hans A
authors: HA
authors: Kretzschmar
authors: Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
authors: Hermann
authors: H
authors: Schätzl
authors: Institute of Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany. Electronic address: martin.groschup@fli.bund.de.
authors: Martin H
authors: MH
authors: Groschup
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D007274:Injections, Intraperitoneal; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018620:PrPSc Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D010879:Piperazines; D018620:PrPSc Proteins; D000077489:Piperazine; D046988:Proteasome Endopeptidase Complex
keywords: Cell assay; Inhibitor; Piperazine; Prion