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Direct interaction of DNMT inhibitors to PrP C suppresses pathogenic process of prion

Title
Direct interaction of DNMT inhibitors to PrP C suppresses pathogenic process of prion
Authors
Kim, Dae-HwanRen, ChunyanRyou, ChongsukLi, Jiaojie
Issue Date
2019-09
Citation
Acta Pharmaceutica Sinica B, 9(5), 952-959
Type
Article
Article Type
Article
Author Keywords
DNMTEpigenetic regulationPrionPrP CTherapeutic compounds
Keywords
PROTEINDISEASESBINDINGDERIVATIVESBETATHERAPEUTICSINFECTIVITYMECHANISMSCONVERSIONAMYLOIDS
ISSN
2211-3835
Abstract
The conversion of the normal cellular prion protein (PrP C )to the misfolded pathogenic scrapie prion protein (PrP Sc )is the biochemical hallmark of prion replication. So far, various chemical compounds that inhibit this conformational conversion have been identified. Here, we report the novel anti-prion activity of SGI-1027 and its meta/meta analogue (M/M), previously known only as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrP Sc in cultured cells with permanent prion infection, without affecting PrP C at the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinders the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrP C , but only SGI-1027 bound to a specific region of PrP C with high affinity, which correlates with its potent anti-prion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrP C . © 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
URI
http://hdl.handle.net/20.500.11750/10776
DOI
10.1016/j.apsb.2019.04.001
Publisher
Chinese Academy of Medical Sciences
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