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Effects of SGI-1027 on Formation and Elimination of PrP Sc in Prion-Infected Cells
Molecular Biology ( IF 1.2 ) Pub Date : 2020-06-17 , DOI: 10.1134/s0026893320030115
J. J. Li , C. S. Ryou , D.-H. Kim

Abstract

Recently, SGI-1027, a well-known inhibitor of DNA-methyl transferases (DNMTs), was reported to effectively reduce formation of pathogenic PrPSc in prion-infected cells. Herein, we confirm the elimination of PrPSc in chronic wasting disease (CWD) prion-infected neurons by SGI-1027, and pinpoint the binding region of human prion protein to SGI-1027. SGI-1027 is broadly functional against various prion disease types, including human prions. Previously, the inhibitory effects of SGI-1027 on DNMT function is well tested in various cell culture models. While neither treatment with a DNMTs enhancer S-adenosyl-L-methionine (SAM), nor with their inhibitor, 5-azacytidine, prevented PrPSc propagation, SGI-1027 did. Our study suggest that the anti-prion effects of SGI-1027 are a result of its direct interaction with PrPC, which effectively interferes with the pathogenic conformational change of PrPC to PrPSc. We conclude that SGI-1027 driven suppression of pathogenic PrPSc is independent of DNMT.


中文翻译:

SGI-1027对Pri病毒感染细胞中PrP Sc的形成和消除的影响

摘要

最近,据报道,众所周知的DNA-甲基转移酶(DNMT)抑制剂SGI-1027可有效减少感染病毒的细胞中病原性PrP Sc的形成。在这里,我们确认通过SGI-1027消除了慢性消耗病(CWD)病毒感染的神经元中的PrP Sc,并确定了人类pin病毒蛋白与SGI-1027的结合区域。SGI-1027具有广泛的功能,可抵抗包括人类病毒在内的各种human病毒疾病。以前,在各种细胞培养模型中都很好地测试了SGI-1027对DNMT功能的抑制作用。虽然用DNMTs增强剂S-腺苷-L-甲硫氨酸(SAM)或其抑制剂5-氮杂胞苷都不能预防PrP Sc传播,SGI-1027做到了。我们的研究表明,SGI-1027的抗-病毒作用是其与PrP C直接相互作用的结果,可有效干扰PrP C向PrP Sc的致病性构象变化。我们得出的结论是,SGI-1027驱动的致病性PrP Sc的抑制独立于DNMT。
更新日期:2020-06-17
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