NR AWWI
AU Phuan,P.W.; Zorn,J.A.; Safar,J.; Giles,K.; Prusiner,S.B.; Cohen,F.E.; May,B.C.H.
TI Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds
QU Journal of General Virology 2007 Apr; 88(4): 1392-401
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB Quinacrine and related 9-aminoacridine compounds are effective in eliminating the alternatively folded prion protein, termed PrPsc, 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 PrPsc, it was inefficient: approximately 5 % of PrPsc was bound under conditions that did not support binding of the cellular isoform, PrPc. Our findings suggest that 9-aminoacridine compounds may reduce the PrPsc burden either by occluding epitopes necessary for templating on the surface of PrPsc or by altering the stability of PrPsc oligomers, where a one-to-one stoichiometry is not necessary.
MH Aminacrine/*metabolism; Animals; Blotting, Western; Cell Line; Cricetinae; Mesocricetus; Mice; Mice, Transgenic; PrPc Proteins/chemistry/isolation & purification/*metabolism; PrPsc Proteins/chemistry/isolation & purification/*metabolism; Prion Diseases/metabolism; Prions/*chemistry/*metabolism; Protein Binding; Protein Folding
AD Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
SP englisch
PO England