Cooperative Orthogonal Macromolecular Assemblies with Broad Spectrum Antiviral Activity, High Selectivity, and Resistance Mitigation
Cooperative Orthogonal Macromolecular Assemblies with Broad Spectrum Antiviral Activity, High Selectivity, and Resistance Mitigation
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DOI：
10.1021/acs.macromol.6b00091
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发表时间：
2016-04-12
期刊：
影响因子：
5.5
通讯作者：
Yang, Yi Yan
中科院分区：
文献类型：
--
作者：
Ichiyama, Koji;Yang, Chuan;Yang, Yi Yan
病毒感染的治疗仍然是难以捉摸的，由于病毒结构的变化（RNA，DNA，包膜和无包膜病毒）以及它们快速突变和获得耐药性的能力。在这里，我们报告了一种使用多功能大分子预防病毒感染的一般策略，所述多功能大分子被设计为具有与病毒竞争免疫细胞的甘露糖部分，以及通过静电相互作用阻断病毒进入并通过中和内体pH来防止病毒复制的碱性胺基。我们表明，用抗病毒聚合物处理的细胞抑制TIM受体运输病毒，可能来自静电和氢键相互作用，EC 50值范围为2.6至6.8 mg/L，取决于TIM受体的类型。分子对接计算揭示了一个意想不到的，一般的，特定的氢键与病毒表面蛋白的相互作用，病毒和细胞结合试验表明，病毒或细胞与抗病毒聚合物孵育后，感染显着减少。此外，甘露糖功能化的大分子有效地阻止了病毒感染免疫细胞。调查了包括登革热、流感、基孔肯雅热、肠道病毒71、埃博拉、马尔堡和单纯疱疹在内的每一类别的代表性病毒，并且在低至0.2 mg/L的聚合物浓度下有效地预防了病毒感染，对哺乳动物细胞具有非常高的选择性（>5000）。这些协同正交相互作用（静电和氢键）的一般性提供了广谱抗病毒活性。由于抗病毒机制是基于氨基酸残基和大分子的甘露糖/阳离子部分之间的非特异性超分子相互作用，因此无论病毒突变如何，都可以形成病毒聚合物和聚合物细胞组装体，从而防止耐药性发展。
Treatment of viral infections continues to be elusive owing to the variance in virus structure (RNA, DNA, and enveloped and nonenveloped viruses) together with their ability to rapidly mutate and garner resistance. Here we report a general strategy to prevent viral infection using multifunctional macromolecules that were designed to have mannose moieties that compete with viruses for immune cells, and basic amine groups that block viral entry through electrostatic interactions and prevent viral replication by neutralizing the endosomal pH. We showed that cells treated with the antiviral polymers inhibited TIM receptors from trafficking virus, likely from electrostatic and hydrogen bonding interactions, with EC50 values ranging from 2.6 to 6.8 mg/L, depending on the type of TIM receptors. Molecular docking computations revealed an unexpected, and general, specific hydrogen-bonding interactions with viral surface proteins, and virus and cell binding assay demonstrated a significant reduction in infection after incubating virus or cells with the antiviral polymers. Moreover, the mannose-functionalized macromolecules effectively prevented the virus from infecting the immune cells. Representative viruses from each category including dengue, influenza, Chikungunya, Enterovirus 71, Ebola, Marburg, and herpes simplex were surveyed, and viral infection was effectively prevented at polymer concentrations as low as 0.2 mg/L with very high selectivity (>5000) over mammalian cells. The generality of these cooperative orthogonal interactions (electrostatic and hydrogen-bonding) provides broad-spectrum antiviral activity. As the antiviral mechanism is based on nonspecific supramolecular interactions between the amino acid residues and mannose/cationic moieties of the macromolecule, the ability to form the virus polymer and polymer cell assemblies can occur regardless of viral mutation, preventing drug resistance development.