NR ACKJ
AU Caughey,W.S.; Raymond,L.D.; Horiuchi,M.; Caughey,B.W.
TI Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines
QU Proceedings of the National Academy of Sciences of the United States of America 1998 Oct 13; 95(21): 12117-22
PT journal article
AB 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, PrPres. Here we identify porphyrins and phthalocyanines as inhibitors of PrPres 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 PrPres formation in a cell-free reaction composed predominantly of hamster PrPres 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 PrPres without apparent cytotoxic effects. The inhibition observed in the cell-free conversion reaction suggests that the mechanism involved direct interactions of the tetrapyrrole with PrPres and/or PrP-sen. These findings introduce a new class of inhibitors of PrPres formation that represents a potential source of therapeutic agents for transmissible spongiform encephalopathies.
MH Cell-Free System; Endopeptidases/*metabolism; Indoles/*pharmacology; Porphyrins/*pharmacology; Prions/*antagonists & inhibitors/biosynthesis
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
SP englisch
PO USA