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Identification of alprenolol hydrochloride as an anti-prion compound using surface plasmon resonance imaging

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Title: Identification of alprenolol hydrochloride as an anti-prion compound using surface plasmon resonance imaging
Other Titles: 表面プラズモン共鳴 (SPR) イメージングを用いたβ遮断薬アルプレノロール塩酸塩の抗プリオン活性の同定
Authors: 宮﨑, 幸子
Authors (alternative): Miyazaki, Yukiko
Issue Date: 20-Mar-2018
Publisher: Springer Science+Business Media
Citation: Nagasaki University (長崎大学), 博士(医学) (2018-03-20)
Abstract: Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for human prion disease remains to be established. In this study, we screened 1200 existing drugs approved by the US Food and Drug Administration (FDA) for anti-prion activity using surface plasmon resonance imaging (SPRi). Of these drugs, 31 showed strong binding activity to recombinant human PrP, and three of these reduced the accumulation of PrPSc in prion-infected cells. One of the active compounds, alprenolol hydrochloride, which is used clinically as a β-adrenergic blocker for hypertension, also reduced the accumulation of PrPSc in the brains of prion-infected mice at the middle stage of the disease when the drug was administered orally with their daily water from the day after infection. Docking simulation analysis suggested that alprenolol hydrochloride fitted into the hotspot within mouse PrPC, which is known as the most fragile structure within the protein. These findings provide evidence that SPRi is useful in identifying effective drug candidates for neurodegenerative diseases caused by abnormal protein aggregation, such as prion diseases.
Description: 長崎大学学位論文 学位記番号:博(医歯薬)甲第1056号 学位授与年月日:平成30年3月20日 / Author: Yukiko Miyazaki, Takeshi Ishikawa, Yuji O. Kamatari, Takehiro Nakagaki, Hanae Takatsuki, Daisuke Ishibashi, Kazuo Kuwata, Noriyuki Nishida, Ryuichiro Atarashi / Citation: Molecular Neurobiology, 56(1), pp.367-377; 2019
Keywords: Prion diseases / Surface plasmon resonance imaging / Alprenolol hydrochloride / Docking simulation
URI: http://hdl.handle.net/10069/39299
ISSN: 08937648
DOI: 10.1007/s12035-018-1088-7
Relational Links: http://hdl.handle.net/10069/38098
Rights: © Springer Science+Business Media, LLC, part of Springer Nature 2018 / The final publication is available at link.springer.com
Type: Thesis or Dissertation
Text Version: ETD
Appears in Collections:dissertation

Citable URI : http://hdl.handle.net/10069/39299

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