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From High‐Throughput Cell Culture Screening to Mouse Model: Identification of New Inhibitor Classes against Prion Disease
Author(s) -
Geissen Markus,
Leidel Fabienne,
Eiden Martin,
Hirschberger Thomas,
Fast Christine,
Bertsch Uwe,
Tavan Paul,
Giese Armin,
Kretzschmar Hans,
Schatzl Hermann M.,
Groschup Martin H.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100119
Subject(s) - scrapie , in vivo , biology , cell culture , bioassay , potency , disease , transmissible spongiform encephalopathy , prion protein , drug discovery , cell , drug , virology , in vitro , pharmacology , medicine , biochemistry , genetics , pathology
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.