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Mol Neurobiol. 2019 Jan;56(1):367-377. doi: 10.1007/s12035-018-1088-7. Epub 2018 Apr 27.

Identification of Alprenolol Hydrochloride as an Anti-prion Compound Using Surface Plasmon Resonance Imaging.

Author information

1
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
2
Program for Nurturing Global Leaders in Tropical and Emerging Infectious Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
3
Molecular Epidemiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
4
Life Science Research Center, Gifu University, Gifu, Japan.
5
Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
6
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
7
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. noriyukinishida@icloud.com.
8
Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. ryuichiro_atarashi@med.miyazaki-u.ac.jp.

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.

KEYWORDS:

Alprenolol hydrochloride; Docking simulation; Prion diseases; Surface plasmon resonance imaging

PMID:
29704200
DOI:
10.1007/s12035-018-1088-7
[Indexed for MEDLINE]

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