The conversion of the normal cellular prion protein(PrP^C) to the misfolded pathogenic scrapie prion protein(Pr PSc) is the biochemical hallmark of prion replication. So far, various chemical compounds that inhibit th...The conversion of the normal cellular prion protein(PrP^C) to the misfolded pathogenic scrapie prion protein(Pr PSc) 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 Pr PSc in cultured cells with permanent prion infection, without affecting PrP^Cat the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a Pr P aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded Pr P aggregates, implying that binding of these compounds hinders the Pr P 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 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 PrP^C.展开更多
基金supported by thegrants from Basic Science Research Program through the National Research Foundation of Korea(NRF-2013R1A1A2011210)Undergraduate Research Program(URP)through Korea Foundation for the Advancement of Science and Creativity(2017030080)+1 种基金supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(HI16C1085 and HI16C0965)the research and development funds of Gwangju Institute of Science and Technology(GK10010,Korea)
文摘The conversion of the normal cellular prion protein(PrP^C) to the misfolded pathogenic scrapie prion protein(Pr PSc) 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 Pr PSc in cultured cells with permanent prion infection, without affecting PrP^Cat the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a Pr P aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded Pr P aggregates, implying that binding of these compounds hinders the Pr P 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 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 PrP^C.
