1. ¹Institute for Neurodegenerative Diseases, University of California, San Francisco, California
2. ²Department of Neurology, University of California, San Francisco, California
3. ³Department of Pharmaceutical Chemistry, University of California, San Francisco, California
4. ⁴Department of Biochemistry and Biophysics, University of California, San Francisco, California

Correspondence: Dr. Stanley B. Prusiner, Institute for Neurodegenerative Diseases, University of California, Box 0518, San Francisco, California 94143-0518. E-mail: stanley@itsa.ucsf.edu

Received 11 April 2003.

Abstract

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.