Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds.
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| Abstract |
Quinacrine and related 9-aminoacridine compounds are effective in eliminating the alternatively folded prion protein, termed PrP(Sc), from scrapie-infected cultured cells. Clinical evaluations of quinacrine for the treatment of human prion diseases are progressing in the absence of a clear understanding of the molecular mechanism by which prion replication is blocked. Here, insight into the mode of action of 9-aminoacridine compounds was sought by using a chemical proteomics approach to target identification. Cellular macromolecules that bind 9-aminoacridine ligands were affinity-purified from tissue lysates by using a 9-aminoacridine-functionalized solid-phase matrix. Although the 9-aminoacridine matrix was conformationally selective for PrP(Sc), it was inefficient: approximately 5 % of PrP(Sc) was bound under conditions that did not support binding of the cellular isoform, PrP(C). Our findings suggest that 9-aminoacridine compounds may reduce the PrP(Sc) burden either by occluding epitopes necessary for templating on the surface of PrP(Sc) or by altering the stability of PrP(Sc) oligomers, where a one-to-one stoichiometry is not necessary.
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| Authors | Puay-Wah Phuan, Julie A Zorn, Jiri Safar, Kurt Giles, Stanley B Prusiner, Fred E Cohen, Barnaby C H May |
| Journal | The Journal of general virology (J Gen Virol) Vol. 88 Issue Pt 4 Pg. 1392-1401 (Apr 2007) ISSN: 0022-1317 [Print] England |
| PMID | 17374787 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Chemical References |
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