Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Instituto de Virología "Dr. J. M. Vanella", Enfermera Gordillo S/N, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Universidad Nacional Córdoba, Facultad Ciencias Químicas, Dpto. Ciencias Farmacéuticas, Haya de La Torre y Medina Allende, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Av. Vélez Sarsfield 1666. CP, X5016GCN, Córdoba, Argentina.
Antiviral Res. 2021 Mar;187:104976. doi: 10.1016/j.antiviral.2020.104976. Epub 2021 Jan 11.
The genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonotic cycle, some of which could lead to human infection. A characteristic of these viruses is their lack of antiviral treatment or vaccine for its prevention. The objective of this work was to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important active compound of Larrea divaricata Cav. (Zigophyllaceae), against Fort Sherman virus (FSV) as a model of Orthobunyavirus genus. At the same time, the effect of NDGA as a lipolytic agent on the cell cycle of this viral model was assessed. The method of reducing plaque forming units on LLC-MK2 cells was used to detect the action of NDGA on CbaAr426 and SFCrEq231 isolates of FSV. NDGA did not show virucidal effect, but it had antiviral activity with a similar inhibition in both isolates, which was dose dependent. It was established that the NDGA has a better inhibition 1-h post-internalization (p.i.), showing a different behavior in each isolate, which was dependent upon the time p.i. Since virus multiplication is dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the 5-lipoxigenase (5-LOX) and the sterol regulatory element-binding proteins (SREBP) pathway. We determined by using caffeic acid, a 5-LOX inhibitor, that the inhibition of this enzyme negatively affected the FSV replication; and by means of resveratrol, a SREBP1 inhibitor, it was showed that the negative regulation of this pathway only had action on the SFCrEq231 reduction. In addition, it was proved that the NDGA acts intracellularly, since it showed the ability to incorporate into LLC-MK2 cells. The information provided in this work converts the NDGA into a compound with antiviral activity in vitro against FSV (Orthobunyavirus), which can be subjected to structural modifications in the future to improve the activity.
正布尼亚病毒属是虫媒病毒属的一组病毒，具有人畜共患循环，其中一些可能导致人类感染。这些病毒的一个特征是缺乏抗病毒治疗或预防疫苗。这项工作的目的是研究 Nordihydroguaiaretic acid（NDGA）的体外抗病毒活性，NDGA 是 Larrea divaricata Cav.（Zygophyllaceae）的最重要活性化合物，作为正布尼亚病毒属的模型，针对 Fort Sherman 病毒（FSV）。同时，评估 NDGA 作为脂解剂对该病毒模型细胞周期的影响。使用 LLC-MK2 细胞中减少蚀斑形成单位的方法检测 NDGA 对 CbaAr426 和 SFCrEq231 分离株 FSV 的作用。NDGA 没有显示出杀病毒作用，但它具有抗病毒活性，在两种分离株中都有相似的抑制作用，这种抑制作用是剂量依赖性的。结果表明，NDGA 在内化后 1 小时（p.i.）具有更好的抑制作用，在每种分离株中表现出不同的行为，这取决于 p.i.时间。由于病毒复制依赖于宿主细胞的脂质代谢，NDGA 的抗病毒作用以前与它扰乱脂质代谢的能力有关，可能通过干扰 5-脂氧合酶（5-LOX）和固醇调节元件结合蛋白（SREBP）途径。我们通过使用咖啡酸（一种 5-LOX 抑制剂）确定，该酶的抑制作用对 FSV 复制有负面影响；并且通过使用白藜芦醇（一种 SREBP1 抑制剂），表明该途径的负调控仅对 SFCrEq231 的减少有作用。此外，还证明 NDGA 在细胞内起作用，因为它显示出能够整合到 LLC-MK2 细胞中。本工作提供的信息将 NDGA 转化为一种具有体外抗 FSV（正布尼亚病毒）活性的化合物，可在未来进行结构修饰以提高活性。
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