Ashiru Omodele, Howe Jonathon D, Butters Terry D
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK.
Virology. 2014 Aug;462-463:135-48. doi: 10.1016/j.virol.2014.05.015. Epub 2014 Jun 25.
Nitazoxanide (NTZ) inhibits influenza, Japanese encephalitis, hepatitis B and hepatitis C virus replication but effects on the replication of other members of the Flaviviridae family has yet to be defined. The pestivirus bovine viral diarrhoea virus (BVDV) is a surrogate model for HCV infection and NTZ induced PKR and eIF2α phosphorylation in both uninfected and BVDV-infected cells. This led to the observation that NTZ depletes ATP-sensitive intracellular Ca(2+) stores. In addition to PKR and eIF2α phosphorylation, consequences of NTZ-mediated Ca(2+) mobilisation included induction of chronic sub-lethal ER stress as well as perturbation of viral protein N-linked glycosylation and trafficking. To adapt to NTZ-mediated ER stress, NTZ treated cells upregulated translation of Ca(2+)-binding proteins, including the ER chaperone Bip and the cytosolic pro-survival and anti-viral protein TCTP. Depletion of intracellular Ca(2+) stores is the primary consequence of NTZ treatment and is likely to underpin all antiviral mechanisms attributed to the thiazolide.
硝唑尼特（NTZ）可抑制流感病毒、日本脑炎病毒、乙型肝炎病毒和丙型肝炎病毒的复制，但对黄病毒科其他成员复制的影响尚未明确。瘟病毒属的牛病毒性腹泻病毒（BVDV）是丙型肝炎病毒感染的替代模型，NTZ在未感染和BVDV感染的细胞中均诱导PKR和eIF2α磷酸化。这导致观察到NTZ耗尽了ATP敏感的细胞内Ca(2+)储备。除了PKR和eIF2α磷酸化外，NTZ介导的Ca(2+)动员的后果还包括诱导慢性亚致死性内质网应激以及干扰病毒蛋白的N-连接糖基化和运输。为了适应NTZ介导的内质网应激，经NTZ处理的细胞上调了Ca(2+)结合蛋白的翻译，包括内质网伴侣蛋白Bip和胞质促生存及抗病毒蛋白TCTP。细胞内Ca(2+)储备的耗尽是NTZ处理的主要后果，可能是该噻唑酰胺类药物所有抗病毒机制的基础。
