Identification of Alprenolol Hydrochloride as an Anti-prion Compound Using Surface Plasmon Resonance Imaging
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.
KeywordsPrion diseases Surface plasmon resonance imaging Alprenolol hydrochloride Docking simulation
We thank Atsuko Matsuo for the technical assistance. This work was supported by JSPS KAKENHI Grant Number JP15H04269 and a grant form Takeda Science Foundation.
We thank Kate Fox, DPhil, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Y.M., N.N., and R.A. designed the entire project. Y.M., T.I., Y.O.K, T.N., H.T., D.I., and K.K. performed the experiments and analyzed the data. N.N. and R.A. supervised and discussed the data. All authors reviewed the manuscript.
Compliance with Ethical Standards
All of these experiments were approved by the Committee on the Animal Care and Use Committees of Nagasaki University. The mice were cared for according to the Guidelines for Animal Experimentation of Nagasaki University
Conflict of Interest
The authors declare that they have no conflicts of interest.
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