Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.
Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.
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DOI：
10.1016/j.antiviral.2016.11.003
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发表时间：
2017-01
影响因子：
7.6
通讯作者：
Babu, Y. S.
中科院分区：
文献类型：
--
作者：
Julander, Justin G.;Siddharthan, Venkatraman;Evans, Joe;Taylor, Ray;Tolbert, Kelsey;Apuli, Chad;Stewart, Jason;Collins, Preston;Gebre, Makda;Neilson, Skot;Van Wettere, Arnaud;Lee, Young-Min;Sheridan, William P.;Morrey, John D.;Babu, Y. S.
寨卡病毒（ZIKV）目前正在出现大流行。虽然疾病通常是亚临床的，但先天性感染后胎儿和新生儿的严重神经系统表现强调了抗病毒干预的迫切需要。腺苷类似物BCX4430对多种RNA病毒具有广谱活性，包括对黄热病、马尔堡病毒和埃博拉病毒的有效体内活性。我们在多种细胞系中测试了该化合物对非洲和亚洲寨卡病毒谱系的细胞病变效应抑制和病毒产量降低试验。为了进一步在相关动物模型中评估其疗效，我们建立了一个严重寨卡病毒感染的小鼠模型，该模型概括了各种人类疾病的表现，包括外周病毒复制、结膜炎、脑炎和脊髓炎。病毒RNA积累的时间过程量化表明，病毒在几个相关组织中有强大的复制，包括在大脑和睾丸中观察到的高和持续的病毒载量。通过感染培养试验和组织切片的免疫组织化学染色，证实了病毒RNA在各种组织中的存在。即使在病毒血症高峰期开始治疗，用BCX4430治疗感染zikv的小鼠也能显著改善结果。BCX4430在致命小鼠模型中对寨卡病毒的有效活性证明了其继续临床开发的必要。
Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development.
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影响因子：
4.9
作者：
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通讯作者：
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作者：
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作者：
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通讯作者：
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