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

Tomomi Imamura, Kyota Fujita, Kazuhiko Tagawa, Teikichi Ikura, Xigui Chen, Hidenori Homma, Takuya Tamura, Ying Mao, Juliana Bosso Taniguchi, Kazumi Motoki, Makoto Nakabayashi, Nobutoshi Ito, Kazunori Yamada, Kentaro Tomii, Hideyuki Okano, Julia Kaye, Steven Finkbeiner, Hitoshi Okazawa

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number33861
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Sep 22

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Small Molecule Libraries
Huntington Disease
Histidine
Computer Simulation
Pharmaceutical Preparations
Diptera
Seeds
Molecular Docking Simulation
Angiotensin III
Digital Libraries
Molecular Targeted Therapy
Chemical Models
Neurons
Oligopeptides
Fluorescence Spectrometry
DNA Repair
DNA Damage
In Vitro Techniques
Body Weight

ASJC Scopus subject areas

  • General

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Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries. / Imamura, Tomomi; Fujita, Kyota; Tagawa, Kazuhiko; Ikura, Teikichi; Chen, Xigui; Homma, Hidenori; Tamura, Takuya; Mao, Ying; Taniguchi, Juliana Bosso; Motoki, Kazumi; Nakabayashi, Makoto; Ito, Nobutoshi; Yamada, Kazunori; Tomii, Kentaro; Okano, Hideyuki; Kaye, Julia; Finkbeiner, Steven; Okazawa, Hitoshi.

In: Scientific Reports, Vol. 6, 33861, 22.09.2016.

Research output: Contribution to journalArticle

Imamura, T, Fujita, K, Tagawa, K, Ikura, T, Chen, X, Homma, H, Tamura, T, Mao, Y, Taniguchi, JB, Motoki, K, Nakabayashi, M, Ito, N, Yamada, K, Tomii, K, Okano, H, Kaye, J, Finkbeiner, S & Okazawa, H 2016, 'Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries', Scientific Reports, vol. 6, 33861. https://doi.org/10.1038/srep33861
Imamura, Tomomi ; Fujita, Kyota ; Tagawa, Kazuhiko ; Ikura, Teikichi ; Chen, Xigui ; Homma, Hidenori ; Tamura, Takuya ; Mao, Ying ; Taniguchi, Juliana Bosso ; Motoki, Kazumi ; Nakabayashi, Makoto ; Ito, Nobutoshi ; Yamada, Kazunori ; Tomii, Kentaro ; Okano, Hideyuki ; Kaye, Julia ; Finkbeiner, Steven ; Okazawa, Hitoshi. / Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries. In: Scientific Reports. 2016 ; Vol. 6.
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