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"From high-throughput cell culture screening to mouse model: Identification of new inhibitor classes against prion disease" Markus Geissen, Fabienne Leidel, Martin Eiden,Thomas Hirschberger, Christine Fast, Uwe Bertsch, Paul Tavan, Armin Giese, Hans A. Kretzschmar, Hermann M. Schätzl, and Martin H. GroschupChemMedChem 6, 1928 – 1937 (2011). Abstract: Transmissible spongiform encephalopathies (TSE) or prion diseases belong to a category of fatal and so far untreatable neurodegenerative diseases. All prion diseases are characterized by both degeneration in the central nervous system in humans and animals in combination with, and the deposition and accumulation of PrPres. Until now, no pharmaceutical product is has been available to cure these diseases or to alleviate the symptoms associated with them. In this study we established a cell culture screening system that allows for a large scaled analysis of certain chemical compounds’ regarding their PrPres inhibitory potential, and received insight intodiscovered structural motifs leading to PrPres clearance at the cellular level. Based on different scrapie-infected cell lines, 10000 substances were tested, which resulted inout of which we identified up to 530 potential inhibitors. After re-screening and validation by using a series of dilutions, 14 substances were identified as being the most effective. These 14 compounds were then used for therapeutic studies in a mouse bioassay to test and verify their potency in vivo. Out of these highly potent inhibitors in cell culture, two compounds exhibited their therapeutic potential by significantly extended extending the survival time of intra-cerebrally infected mice, when applied 90 days after the mice’s initial infection with scrapie, emphasizing their therapeutic potential. BMO authors (in alphabetic order): Thomas Hirschberger Paul Tavan |
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Letzte Änderung: 2016-09-14 13:34
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