Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie.
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.
Kocisko
David A
DA
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
Engel
Abbi L
AL
Harbuck
Kristin
K
Arnold
Kevin M
KM
Olsen
Emily A
EA
Raymond
Lynne D
LD
Vilette
Didier
D
Caughey
Byron
B
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*
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