title: From high-throughput cell culture screening to mouse model: identification of new inhibitor classes against prion disease.
abstract: Transmissible spongiform encephalopathies (TSE) or prion diseases belong to a category of fatal and so far untreatable neurodegenerative conditions. All prion diseases are characterized by both degeneration in the central nervous system (CNS) in humans and animals and the deposition and accumulation of Proteinase K-resistant prion protein (PrP(res)). Until now, no pharmaceutical product has been available to cure these diseases or to alleviate their associated symptoms. Here, a cell-culture screening system is described that allows for the large-scale analysis of the PrP(res) inhibitory potential of a library of compounds and the identification of structural motifs leading potent compounds able to cause PrP(res) clearance at the cellular level. Based on different scrapie-infected cell lines, 10,000 substances were tested, out of which 530 potential inhibitors were identified. After re-screening and validation using a series of dilutions, 14 compounds were identified as the most effective. These 14 compounds were then used for therapeutic studies in a mouse bioassay to test and verify their in vivo potency. Two compounds exhibited therapeutic potential in the mouse model by significantly extending the survival time of intracerebrally infected mice, when treated 90 days after infection with scrapie.
authors.affiliation: Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute for Novel and Emerging Infectious Diseases, Suedufer 10, 17493 Greifswald-Insel Riems, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Geissen
authors.forename: Fabienne
authors.initials: F
authors.lastname: Leidel
authors.forename: Martin
authors.initials: M
authors.lastname: Eiden
authors.forename: Thomas
authors.initials: T
authors.lastname: Hirschberger
authors.forename: Christine
authors.initials: C
authors.lastname: Fast
authors.forename: Uwe
authors.initials: U
authors.lastname: Bertsch
authors.forename: Paul
authors.initials: P
authors.lastname: Tavan
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Schatzl
authors.forename: Martin H
authors.initials: MH
authors.lastname: Groschup
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D051379:Mice; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D012608:Scrapie / Q000188:drug therapy; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018620:PrPSc Proteins; D054852:Small Molecule Libraries