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Quinoline Derivatives Are Therapeutic Candidates for Transmissible Spongiform Encephalopathies

Ikuko Murakami-Kubo,^1,2* Katsumi Doh-ura,^1* Kensuke Ishikawa,¹ Satoshi Kawatake ,^1, Kensuke Sasaki,¹ Jun-ichi Kira,² Shigeru Ohta,³ and Toru Iwaki¹

Departments of Neuropathology,¹ Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582,² Department of Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8551, Japan³

Received 2 June 2003/ Accepted 8 October 2003

We previously reported that quinacrine inhibited the formation of an abnormal prion protein (PrPres), a key molecule in the pathogenesis of transmissible spongiform encephalopathy, or prion disease, in scrapie-infected neuroblastoma cells. To elucidate the structural aspects of its inhibiting action, various chemicals with a quinoline ring were screened in the present study. Assays of the scrapie-infected neuroblastoma cells revealed that chemicals with a side chain containing a quinuclidine ring at the 4 position of a quinoline ring (represented by quinine) inhibited the PrPres formation at a 50% inhibitory dose ranging from 10^-1 to 10¹ µM. On the other hand, chemicals with a side chain at the 2 position of a quinoline ring (represented by 2,2'-biquinoline) more effectively inhibited the PrPres formation at a 50% inhibitory dose ranging from 10^-3 to 10^-1 µM. A metabolic labeling study revealed that the action of quinine or biquinoline was not due to any alteration in the biosynthesis or turnover of normal prion protein, whereas surface plasmon resonance analysis showed a strong binding affinity of biquinoline with a recombinant prion protein. In vivo studies revealed that 4-week intraventricular infusion of quinine or biquinoline was effective in prolonging the incubation period in experimental mouse models of intracerebral infection. The findings suggest that quinoline derivatives with a nitrogen-containing side chain have the potential of both inhibiting PrPres formation in vitro and prolonging the incubation period of infected animals. These chemicals are new candidates for therapeutic drugs for use in the treatment of transmissible spongiform encephalopathies.

Present address: Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

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