title: Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie.
abstract: The transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases. A primary therapeutic target for TSE intervention has been a protease-resistant form of prion protein known as PrP(Sc) or PrP-res. In vitro testing of mouse scrapie-infected cell cultures has identified many PrP-res inhibitors that also have activity in vivo. Here we identify 32 new inhibitors of two strains of mouse scrapie PrP-res. Furthermore, to investigate the species-specificity of these and other PrP-res inhibitors, we have developed a high-throughput cell culture assay based on Rov9 cells chronically-infected with sheep scrapie. Of 32 inhibitors of murine PrP-res that were also tested in the Rov9 cells, only six showed inhibitory activity against sheep PrP-res. The three most potent inhibitors of both murine and ovine PrP-res formation (with 50% inhibition at < or =5 microM) were tannic acid, pentosan polysulfate and Fe(III) deuteroporphyrin 2,4-bisethyleneglycol. The latter two have anti-mouse scrapie activity in vivo. These results identify new inhibitors of murine and ovine PrP-res formation and reinforce the idea that compounds effective against PrP-res from one species or strain cannot be assumed to be active against others.
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA. DKocisko@niaid.nih.gov
authors.forename: David A
authors.initials: DA
authors.lastname: Kocisko
authors.forename: Abbi L
authors.initials: AL
authors.lastname: Engel
authors.forename: Kristin
authors.initials: K
authors.lastname: Harbuck
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Arnold
authors.forename: Emily A
authors.initials: EA
authors.lastname: Olsen
authors.forename: Lynne D
authors.initials: LD
authors.lastname: Raymond
authors.forename: Didier
authors.initials: D
authors.lastname: Vilette
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
mesh_terms: D000818:Animals; D002460:Cell Line; D003905:Deuteroporphyrins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology; D005290:Ferric Compounds / Q000494:pharmacology; D051379:Mice; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D012608:Scrapie / Q000188:drug therapy* / Q000378:metabolism*; D012756:Sheep; D013045:Species Specificity; D013634:Tannins / Q000494:pharmacology*
chemical_list: D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D018620:PrPSc Proteins; D013634:Tannins; C404818:deuteroporphyrin IX 2,4-bis(ethylene glycol)iron III; D010426:Pentosan Sulfuric Polyester