Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that lack therapeutic solutions. Here, we show that the molecular chaperone (N,N′-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide)), designed via docking simulations, molecular dynamics simulations and quantum chemical calculations, slows down the progress of TSEs. In vitro, the designer molecular chaperone stabilizes the normal cellular prion protein, eradicates prions in infected cells, prevents the formation of drug-resistant strains and directly inhibits the interaction between prions and abnormal aggregates, as shown via real-time quaking-induced conversion and in vitro conversion NMR. Weekly intraperitoneal injection of the chaperone in prion-infected mice prolonged their survival, and weekly intravenous administration of the compound in macaques infected with bovine TSE slowed down the development of neurological and psychological symptoms and reduced the concentration of disease-associated biomarkers in the animals’ cerebrospinal fluid. The de novo rational design of chaperone compounds could lead to therapeutics that can bind to different prion protein strains to ameliorate the pathology of TSEs.

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The PAICS codes are available at www.paics.net/index_e.html.

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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

We thank M. Fukushima at the Translational Research Informatics Center and H. Mizusawa at the National Center of Neurology and Psychiatry for fruitful discussion. We also thank R. Honda, T. Saeki, M. Horii and S. Hori for providing technical help. K.K. was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by grants from the Ministry of Health, Labour and Welfare. The study was also supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development.

Author information

Author notes

    • Keiichi Yamaguchi

    Present address: Institute for Protein Research, Osaka University, Osaka, Japan

    • Fumiko Ono

    Present address: Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Japan

    • Hiroaki Shibata

    Present address: Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke, Japan

    • Takeshi Ishikawa

    Present address: Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Japan

  1. These authors contributed equally: Keiichi Yamaguchi, Yuji O. Kamatari, Fumiko Ono, Takayuki Fuse.

Affiliations

  1. Center for Emerging Infectious Diseases, Gifu University, Gifu, Japan

    • Keiichi Yamaguchi
    • , Yuji O. Kamatari
    • , Abdelazim Elsayed Elhelaly
    • , Mayuko Fukuoka
    • , Tsutomu Kimura
    • , Junji Hosokawa-Muto
    • , Takeshi Ishikawa
    •  & Kazuo Kuwata
  2. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    • Keiichi Yamaguchi
    • , Abdelazim Elsayed Elhelaly
    • , Mayuko Fukuoka
    •  & Kazuo Kuwata
  3. Life Science Research Center, Gifu University, Gifu, Japan

    • Yuji O. Kamatari
  4. Faculty of Animal Crisis Management, Chiba Institute of Science, Choshi, Japan

    • Fumiko Ono
  5. Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan

    • Hiroaki Shibata
  6. Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    • Takayuki Fuse
    • , Takeshi Ishikawa
    • , Daisuke Ishibashi
    •  & Noriyuki Nishida
  7. Department of Food Hygiene and Control, Faculty of Veterinary Medicine, Suez Canal University, Ismalia, Egypt

    • Abdelazim Elsayed Elhelaly
  8. Department of Chemistry, Faulty of Science Division II, Tokyo University of Science, Tokyo, Japan

    • Tsutomu Kimura
  9. First Department of Forsenic Science, National Research Institute of Police Science, Kashiwa, Japan

    • Junji Hosokawa-Muto
  10. Department of Pathology, National Institute of Infectious Disease, Tokyo, Japan

    • Minoru Tobiume
  11. Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    • Yoshinori Takeuchi
    •  & Yutaka Matsuyama
  12. Department of Gene and Development, Graduate School of Medicine, Gifu University, Gifu, Japan

    • Kazuo Kuwata

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Contributions

K.Y. prepared the 15N-labelled and non-labelled recombinant prions, and performed the IVC-NMR measurements and analysis. Y.O.K. measured and analysed the binding data using NMR and SPR. F.O. and H.S. conducted the in vivo treatment study. D.I. and M.T. conducted the pathological examinations for mice and macaques, respectively. T.F. and N.N. analysed Tau proteins in the central nervous system. T.K. established the method for the synthesis of the anti-prion compounds. J.H-M., A.E.E. and M.F. performed the in vitro, ex vivo and in vivo experiments. T.I. coded the FMO programme PAICS using the programming language C. Y.T. and Y.M. performed the statistical analysis. K.K. supervised the project, analysed the data and wrote the manuscript.

Competing interests

The authors declare no conflicts of interest.

Corresponding author

Correspondence to Kazuo Kuwata.

Supplementary information

  1. Supplementary Information

    Supplementary figures and tables.

  2. Reporting summary

  3. Supplementary Video 1

    Prion infected macaque (number 6, control) at 19.7 m.p.i.

  4. Supplementary Video 2

    Prion infected macaque (number 3, BOS) at 19.7 m.p.i.

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https://doi.org/10.1038/s41551-019-0349-8