Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines.
A central aspect of pathogenesis in the transmissible spongiform encephalopathies or prion diseases is the conversion of normal protease-sensitive prion protein (PrP-sen) to the abnormal protease-resistant form, PrP-res. Here we identify porphyrins and phthalocyanines as inhibitors of PrP-res accumulation. The most potent of these tetrapyrroles had IC50 values of 0.5-1 microM in scrapie-infected mouse neuroblastoma (ScNB) cell cultures. Inhibition was observed without effects on protein biosynthesis in general or PrP-sen biosynthesis in particular. Tetrapyrroles also inhibited PrP-res formation in a cell-free reaction composed predominantly of hamster PrP-res and PrP-sen. Inhibitors were found among phthalocyanines, deuteroporphyrins IX, and meso-substituted porphines; examples included compounds containing anionic, neutral protic, and cationic peripheral substituents and various metals. We conclude that certain tetrapyrroles specifically inhibit the conversion of PrP-sen to PrP-res without apparent cytotoxic effects. The inhibition observed in the cell-free conversion reaction suggests that the mechanism involved direct interactions of the tetrapyrrole with PrP-res and/or PrP-sen. These findings introduce a new class of inhibitors of PrP-res formation that represents a potential source of therapeutic agents for transmissible spongiform encephalopathies.
Caughey
W S
WS
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Raymond
L D
LD
Horiuchi
M
M
Caughey
B
B
D002474:Cell-Free System; D010450:Endopeptidases / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D011166:Porphyrins / Q000494:pharmacology*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D007211:Indoles; D054833:Isoindoles; D011166:Porphyrins; D011328:Prions; D010450:Endopeptidases; C013647:phthalocyanine