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.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Miyazaki Y,Ishikawa T,Kamatari YO,Nakagaki T,Takatsuki H,Ishibashi D,Kuwata K,Nishida N,Atarashi Rdoi
10.1007/s12035-018-1088-7subject
Has Abstractpub_date
2019-01-01 00:00:00pages
367-377issue
1eissn
0893-7648issn
1559-1182pii
10.1007/s12035-018-1088-7journal_volume
56pub_type
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