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（BVDV）是黄病毒科 Pestivirus 属的一种病毒。该病毒可导致牛只发生急性及持续性感染，每年给畜牧业带来巨额经济损失。全球范围内持续性 BVDV 感染的高发态势以及高效抗病毒疗法的匮乏，促使制药行业加大力度，致力于发现和开发新型的抗 BVDV 疗法。针对病毒包膜蛋白的抗病毒靶向是治疗病毒感染的有效策略。本研究通过前瞻性的小分子高通量对接，以识别可能结合于 BVDV 包膜蛋白 E2 的 I 和 II 结构域之间的区域的分子。我们购买了或合成了结构各异的化合物，并对其进行了抗 BVDV 活性的检测。其中五种化合物表现出活性，其 IC50 值处于低至中微摩尔范围。对于这些化合物，我们通过分子动力学模拟对其可能的结合决定因素进行了表征。在活性分子与 E2 结合位点氨基酸残基之间的相互作用中，观察到了一种共同的相互作用模式。这些发现有助于更好地理解 BVDV E2 与这些抑制剂之间的相互作用，同时也有利于新型、更强效的 BVDV 抗病毒药物的发现。