Differential inhibition of prion propagation by enantiomers of quinacrine.
Prion diseases are fatal neurologic disorders caused by accumulation of a pathogenic isoform (PrP(Sc)) of the prion protein (PrP). The recent discovery of the inhibitory action of quinacrine on PrP(Sc) formation in scrapie-infected neuroblastoma (ScN2a) cells raised the possibility of a treatment for patients with prion disease. To investigate the efficacy of quinacrine enantiomers, we measured the inhibitory effect of these isomers on PrP(Sc) formation in ScN2a cells. (S)-quinacrine exhibited superior antiprion activity compared with (R)-quinacrine and two generic quinacrines that appear to be racemates. Treatment with these various forms of quinacrine did not induce adverse changes affecting cell survival and the expression of marker proteins over a range of potentially therapeutic concentrations. Thus, quinacrine enantiomers demonstrated stereoselectivity on prion elimination but not cytotoxicity in ScN2a cells. Our results raise the possibility that in vivo treatment using one enantiomer of quinacrine may be superior to a racemic mixture, which is the form that is generally used when quinacrine is employed to treat parasitic diseases.
Ryou
Chongsuk
C
Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143-0518, USA.
Legname
Giuseppe
G
Peretz
David
D
Craig
John C
JC
Baldwin
Michael A
MA
Prusiner
Stanley B
SB
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007700:Kinetics; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D011328:Prions / Q000037:antagonists & inhibitors*; D011796:Quinacrine / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D018620:PrPSc Proteins; D011328:Prions; D011796:Quinacrine