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Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds

¹ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
² Department of Neurology, University of California San Francisco, San Francisco, CA, USA
³ Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA
⁴ Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA

Correspondence
Barnaby C. H. May
bmay{at}ind.ucsf.edu

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.

Supplementary material is available in JGV Online.

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