{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:07:40Z","timestamp":1791328060922,"version":"4.3.1"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,6,2]],"date-time":"2006-06-02T00:00:00Z","timestamp":1149206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2006,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prion diseases are invariably fatal, neurodegenerative diseases transmitted by an infectious agent, PrP<jats:sup>Sc<\/jats:sup>, a pathogenic, conformational isoform of the normal prion protein (PrP<jats:sup>C<\/jats:sup>). Heterocyclic compounds such as acridine derivatives like quinacrine abolish prion infectivity in a cell culture model of prion disease. Here, we report that these compounds execute their antiprion activity by redistributing cholesterol from the plasma membrane to intracellular compartments, thereby destabilizing membrane domains. Our findings are supported by the fact that structurally unrelated compounds with known cholesterol\u2010redistributing effects \u2013 U18666A, amiodarone, and progesterone \u2013 also possessed high antiprion potency. We show that tricyclic antidepressants (e.g. desipramine), another class of heterocyclic compounds, displayed structure\u2010dependent antiprion effects and enhanced the antiprion effects of quinacrine, allowing lower doses of both drugs to be used in combination. Treatment of ScN2a cells with quinacrine or desipramine induced different ultrastructural and morphological changes in endosomal compartments. We synthesized a novel drug from quinacrine and desipramine, termed quinpramine, that led to a fivefold increase in antiprion activity compared to quinacrine with an EC<jats:sub>50<\/jats:sub> of 85\u2003n<jats:sc>m<\/jats:sc>. Furthermore, simvastatin, an inhibitor of cholesterol biosynthesis, acted synergistically with both heterocyclic compounds to clear PrP<jats:sup>Sc<\/jats:sup>. Our data suggest that a cocktail of drugs targeting the lipid metabolism that controls PrP conversion may be the most efficient in treating Creutzfeldt\u2010Jakob disease.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03889.x","type":"journal-article","created":{"date-parts":[[2006,6,6]],"date-time":"2006-06-06T20:43:36Z","timestamp":1149626616000},"page":"748-759","source":"Crossref","is-referenced-by-count":74,"title":["Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent\u2010resistant membrane compartments"],"prefix":"10.1111","volume":"98","author":[{"given":"Ralf","family":"Klingenstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"L\u00f6ber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka","family":"Kujala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Godsave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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