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.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
W S
WS
Caughey
L D
LD
Raymond
M
M
Horiuchi
B
B
Caughey
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