DataSheet1.pdf

Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC50 values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.

牛病毒性腹泻病毒（Bovine viral diarrhea virus, BVDV）是黄病毒科（Flaviviridae）瘟病毒属（Pestivirus）的成员。BVDV可引发牛的急性与持续性感染，每年给畜牧业造成巨额经济损失。全球持续性BVDV感染的流行态势，以及当前缺乏高效抗病毒治疗手段的现状，推动了制药行业大力研发新型抗BVDV疗法的工作。靶向病毒包膜蛋白的抗病毒策略，是干预病毒感染的有效治疗手段。本研究采用前瞻性小分子高通量对接技术，筛选出可能结合BVDV包膜蛋白E2的I、II结构域所界定区域的候选分子。研究人员采购或合成了多种结构迥异的化合物，并针对其抗BVDV活性进行了活性检测。其中5种筛选得到的化合物具有抗病毒活性，其半最大效应浓度（IC50）处于低至中微摩尔的浓度区间。针对这些活性化合物，研究人员通过分子动力学模拟表征了其潜在的结合决定位点。研究观察到，活性分子与E2蛋白结合位点内的氨基酸残基之间存在共通的相互作用模式。本研究结果有助于更深入地解析BVDV E2蛋白与这类抑制剂的相互作用机制，同时可为新型、更高效的抗BVDV药物的研发提供有益参考。