1887

Abstract

Quinacrine and related 9-aminoacridine compounds are effective in eliminating the alternatively folded prion protein, termed PrP, 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, it was inefficient: approximately 5 % of PrP was bound under conditions that did not support binding of the cellular isoform, PrP. Our findings suggest that 9-aminoacridine compounds may reduce the PrP burden either by occluding epitopes necessary for templating on the surface of PrP or by altering the stability of PrP oligomers, where a one-to-one stoichiometry is not necessary.

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2007-04-01
2019-11-18
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vol. , part 4, pp. 1392 – 1401

Selectivity of PrP precipitation by a solid-phase matrix is influenced by the nature of the detergent used to prepare the cell lysate.

The acridine-ligated matrix fails to affinity-purify the GPI-anchored protein Thy-1.

Comparison of ligand bioactivity in ScN2a cells and ability to affinity-purify PrP .

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