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 authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information.
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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.
The authors declare no conflicts of interest.
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Yamaguchi, K., Kamatari, Y.O., Ono, F. et al. A designer molecular chaperone against transmissible spongiform encephalopathy slows disease progression in mice and macaques. Nat Biomed Eng 3, 206–219 (2019). https://doi.org/10.1038/s41551-019-0349-8
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