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Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines.

Abstract
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.
AuthorsW S Caughey, L D Raymond, M Horiuchi, B Caughey
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 21 Pg. 12117-22 (Oct 13 1998) ISSN: 0027-8424 [Print] United States
PMID9770449 (Publication Type: Journal Article)
Chemical References
  • Indoles
  • Isoindoles
  • Porphyrins
  • Prions
  • Endopeptidases
  • phthalocyanine
Topics
  • Cell-Free System
  • Endopeptidases (metabolism)
  • Indoles (pharmacology)
  • Isoindoles
  • Porphyrins (pharmacology)
  • Prions (antagonists & inhibitors, biosynthesis)

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