Durantel D, Branza-Nichita N, Carrouée-Durantel S, Butters T D, Dwek R A, Zitzmann N
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
J Virol. 2001 Oct;75(19):8987-98. doi: 10.1128/JVI.75.19.8987-8998.2001.
The glucose-derived iminosugar derivatives N-butyl- and N-nonyl-deoxynojirimycin (DNJ) have an antiviral effect against a broad spectrum of viruses including Bovine viral diarrhea virus (BVDV). For BVDV, this effect has been attributed to the reduction of viral secretion due to an impairment of viral morphogenesis caused by the ability of DNJ-based iminosugar derivatives to inhibit ER alpha-glucosidases (N. Zitzmann, A. S. Mehta, S. Carrouée, T. D. Butters, F. M. Platt, J. McCauley, B. S. Blumberg, R. A. Dwek, and T. M. Block, Proc. Natl. Acad. Sci. USA 96:11878-11882, 1999). Here we present the antiviral features of newly designed DNJ derivatives and report for the first time the antiviral activity of long-alkyl-chain derivatives of deoxygalactonojirimycin (DGJ), a class of iminosugars derived from galactose which does not inhibit endoplasmic reticulum (ER) alpha-glucosidases. We demonstrate the lack of correlation between the ability of long-alkyl-chain DNJ derivatives to inhibit ER alpha-glucosidases and their antiviral effect, ruling out ER alpha-glucosidase inhibition as the sole mechanism responsible. Using short- and long-alkyl-chain DNJ and DGJ derivatives, we investigated the mechanisms of action of these drugs. First, we excluded their potential action at the level of the replication, protein synthesis, and protein processing. Second, we demonstrated that DNJ derivatives cause both a reduction in viral secretion and a reduction in the infectivity of newly released viral particles. Long-alkyl-chain DGJ derivatives exert their antiviral effect solely via the production of viral particles with reduced infectivity. We demonstrate that long-alkyl-chain DNJ and DGJ derivatives induce an increase in the quantity of E2-E2 dimers accumulated within the ER. The subsequent enrichment of these homodimers in secreted virus particles correlates with their reduced infectivity.
葡萄糖衍生的亚氨基糖衍生物N-丁基-和N-壬基-脱氧野尻霉素（DNJ）对包括牛病毒性腹泻病毒（BVDV）在内的多种病毒具有抗病毒作用。对于BVDV，这种作用归因于基于DNJ的亚氨基糖衍生物抑制内质网α-葡萄糖苷酶的能力导致病毒形态发生受损，从而减少了病毒分泌（N.齐茨曼、A.S.梅塔、S.卡鲁埃、T.D.巴特斯、F.M.普拉特、J.麦考利、B.S.布隆伯格、R.A.德韦克和T.M.布洛克，《美国国家科学院院刊》96:11878 - 11882，1999）。在此，我们展示了新设计的DNJ衍生物的抗病毒特性，并首次报告了脱氧半乳糖野尻霉素（DGJ）的长烷基链衍生物的抗病毒活性，DGJ是一类源自半乳糖的亚氨基糖，不抑制内质网（ER）α-葡萄糖苷酶。我们证明了长烷基链DNJ衍生物抑制ERα-葡萄糖苷酶的能力与其抗病毒作用之间缺乏相关性，排除了ERα-葡萄糖苷酶抑制是唯一作用机制的可能性。使用短烷基链和长烷基链的DNJ及DGJ衍生物，我们研究了这些药物的作用机制。首先，我们排除了它们在复制、蛋白质合成和蛋白质加工水平的潜在作用。其次，我们证明DNJ衍生物既会导致病毒分泌减少，也会使新释放的病毒颗粒的感染性降低。长烷基链DGJ衍生物仅通过产生感染性降低的病毒颗粒发挥其抗病毒作用。我们证明长烷基链DNJ和DGJ衍生物会导致内质网内积累的E2 - E2二聚体数量增加。这些同型二聚体随后在分泌的病毒颗粒中的富集与其降低的感染性相关。
