title: Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries.
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.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.affiliation: Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Xigui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Homma
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Juliana Bosso
authors.initials: JB
authors.lastname: Taniguchi
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Motoki
authors.affiliation: Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakabayashi
authors.affiliation: Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.affiliation: Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-8579, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamada
authors.affiliation: 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.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tomii
authors.affiliation: Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 112-0012, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Kaye
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa