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Sci Rep. 2016 Sep 22;6:33861. doi: 10.1038/srep33861.

Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries.

Author information

1
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
2
Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
3
Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-8579, Japan.
4
Cellular System Analysis Team, Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7, Aomi, Koto-ku, Tokyo 135-0064, Japan.
5
Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 112-0012, Japan.
6
Taube/Koret Center for Neurodegenerative Disease, Gladstone Institute of Neurological Disease, and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco CA 94158, USA.
7
Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Abstract

We identified drug seeds for treating Huntington's disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD.

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