beta-d-N (4) -Hydroxycytidine强有力的Anti-alphavirus化合物,产生高水平的突变病毒基因组。
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克罗斯曼Urakova N,库兹涅佐娃V, DK, Sokratian, Guthrie DB, Kolykhalov AA,马洛克伍德,Natchus MG,克劳利先生,画家GR, Frolova EI, Frolov我
beta-d-N (4) -Hydroxycytidine强有力的Anti-alphavirus化合物,产生高水平的突变病毒基因组。
J微生物学报。2018年1月17日,92 (3)。pii: JVI.01965-17。doi: 10.1128 / JVI.01965-17。打印2018 2月1。
- PubMed ID
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29167335 (在PubMed]
- 文摘
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委内瑞拉马脑炎病毒(VEEV)是一个新的世界的代表成员再。它是由蚊子传播的载体,引起人类的高度使人虚弱的疾病,马科动物和其他脊椎动物宿主。尽管连续的公共卫生威胁,很少与anti-VEEV活动化合物在细胞培养和小鼠模型已确定到目前为止,病毒耐药性的快速发展,其中一些已被记录。在这项研究中,我们调查了使用修改后的核苷模拟的可能性,beta-d-N (4) -hydroxycytidine (NHC),作为anti-VEEV剂及其anti-VEEV活动定义的机制。结果表明,NHC是一个非常强有力的抗病毒因子。它影响基因组的释放RNA-containing v字形的病毒粒子及其传染性。这两种抗病毒活动是由NHC-induced积累的突变病毒特异性rna。抗病毒效果最突出NHC时在感染过程的早期,在放大- - -正链rna在感染细胞。最重要的是,只有低级阻力VEEV NHC可以开发,和它需要收购和合作多个突变nsP4的函数。这些适应性突变密切位于相同的nsP4段。 Our data suggest that NHC is more potent than ribavirin as an anti-VEEV agent and likely can be used to treat other alphavirus infections.IMPORTANCE Venezuelan equine encephalitis virus (VEEV) can cause widespread epidemics among humans and domestic animals. VEEV infections result in severe meningoencephalitis and long-term sequelae. No approved therapeutics exist for treatment of VEEV infections. Our study demonstrates that beta-d-N (4)-hydroxycytidine (NHC) is a very potent anti-VEEV compound, with the 50% effective concentration being below 1 muM. The mechanism of NHC antiviral activity is based on induction of high mutation rates in the viral genome. Accordingly, NHC treatment affects both the rates of particle release and the particle infectivity. Most importantly, in contrast to most of the anti-alphavirus drugs that are under development, resistance of VEEV to NHC develops very inefficiently. Even low levels of resistance require acquisition of multiple mutations in the gene of the VEEV-specific RNA-dependent RNA polymerase nsP4.
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