Quinoline Derivatives Are Therapeutic Candidates for Transmissible Spongiform Encephalopathies

Ikuko Murakami-Kubo, Katsumi Doh-Ura, Kensuke Ishikawa, Satoshi Kawatake, Kensuke Sasaki, Jun Ichi Kira, Shigeru Ohta, Toru Iwaki

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Abstract

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 of 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.

Original languageEnglish
Pages (from-to)1281-1288
Number of pages8
JournalJournal of virology
Volume78
Issue number3
DOIs
Publication statusPublished - Feb 1 2004

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Murakami-Kubo, I., Doh-Ura, K., Ishikawa, K., Kawatake, S., Sasaki, K., Kira, J. I., Ohta, S., & Iwaki, T. (2004). Quinoline Derivatives Are Therapeutic Candidates for Transmissible Spongiform Encephalopathies. Journal of virology, 78(3), 1281-1288. https://doi.org/10.1128/JVI.78.3.1281-1288.2004