Original articles
Dae-Hwan Kim, Chunyan Ren, Chongsuk Ryou, Jiaojie Li. Direct interaction of DNMT inhibitors to PrPC suppresses pathogenic process of prion[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 952-959

Direct interaction of DNMT inhibitors to PrPC suppresses pathogenic process of prion
Dae-Hwan Kima,b, Chunyan Renc, Chongsuk Ryoua,d, Jiaojie Lie
a Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Republic of Korea;
b School of Undergraduate Studies, College of Transdisciplinary Studies, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea;
c Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA;
d Department of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea;
e Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
The conversion of the normal cellular prion protein (PrPC) to the misfolded pathogenic scrapie prion protein (PrPSc) 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 PrPSc in cultured cells with permanent prion infection, without affecting PrPC 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 PrPC, but only SGI-1027 bound to a specific region of PrPC with high affinity, which correlates with its potent antiprion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential antiprion agents that preferentially function through direct interaction with PrPC.
Key words:    Prion    DNMT    Therapeutic compounds    PrPC    Epigenetic regulation   
Received: 2018-12-27     Revised: 2019-03-17
DOI: 10.1016/j.apsb.2019.04.001
Funds: We thank Keun-Hey Ki, Hye-mi Lee, Jihyun. Lee, Trang H. T. Trinh and Sungeun Lee for their help on RNA extraction, protein expression and purification. This research was supported by the grants from Basic Science Research Program through the National Research Foundation of Korea (NRF-2013R1A1A2011210), and Undergraduate Research Program (URP) through Korea Foundation for the Advancement of Science and Creativity (2017030080). This work was also supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI16C1085 and HI16C0965) and the research and development funds of Gwangju Institute of Science and Technology (GK10010, Korea).
Corresponding author: Chongsuk Ryou, Jiaojie Li     Email:cryou2@hanyang.ac.kr;jjli@gist.ac.kr
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Dae-Hwan Kim
Chunyan Ren
Chongsuk Ryou
Jiaojie Li

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