Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
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DOI：
10.1016/j.biomaterials.2017.05.028
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发表时间：
2017-09-01
期刊：
影响因子：
14
通讯作者：
Haag, Rainer
中科院分区：
文献类型：
--
作者：
Bhatia, Sumati;Lauster, Daniel;Haag, Rainer
通过多价唾液酸抑制剂阻止病毒血凝素与呼吸道宿主细胞的结合来抑制甲型流感病毒感染是一种很有前途的策略。然而，多价支架的最佳几何形状和最佳配体呈现在体外和体内的有效抑制应用仍不清楚。在这里，通过比较线性和树突状聚甘油唾液苷（lpsa和dPGSA），我们确定了高效流感病毒A/X31/1 （H3N2）多价抑制剂的结构要求和最佳配体密度。由于其体积大，在最佳配体密度下，lpsa对病毒的立体屏蔽效果明显优于树突状类似物。统计力学模型合理化了配体密度、形态和多价支架大小与抑制病毒细胞结合潜力的相关性。优化后的lpsa在低纳摩尔浓度范围内抑制病毒感染的IC50，对感染后的A/Mallard/439/2004 （H3N2）和A/turkey/Italy/472/1999 （H7N1）禽流感病毒也有较强的抗病毒活性。抑制剂的体内应用清楚地证实了线性多价支架在预防感染方面具有较高的抑制潜力。优化后的lpsa在体内无任何急性毒性，且比神经氨酸酶抑制剂羧化奥司他韦更有效。lpsa与羧酸奥司他韦联合应用显示出协同抑制作用，成功地预防了小鼠流感病毒感染。(C) 2017 Elsevier Ltd.版权所有。
Inhibition of influenza A virus infection by multivalent sialic acid inhibitors preventing viral hemagglutinin binding to host cells of the respiratory tract is a promising strategy. However, optimal geometry and optimal ligand presentation on multivalent scaffolds for efficient inhibition both in vitro and in vivo application are still unclear. Here, by comparing linear and dendritic polyglycerol sialosides (LPGSA and dPGSA) we identified architectural requirements and optimal ligand densities for an efficient multivalent inhibitor of influenza virus A/X31/1 (H3N2). Due to its large volume, the LPGSA at optimal ligand density sterically shielded the virus significantly better than the dendritic analog. A statistical mechanics model rationalizes the relevance of ligand density, morphology, and the size of multivalent scaffolds for the potential to inhibit virus-cell binding. Optimized LPGSA inhibited virus infection at IC50 in the low nanomolar nanoparticle concentration range and also showed potent antiviral activity against two avian influenza strains A/Mallard/439/2004 (H3N2) and A/turkey/Italy/472/1999 (H7N1) post infection. In vivo application of inhibitors clearly confirmed the higher inhibition potential of linear multivalent scaffolds to prevent infection. The optimized LPGSA did not show any acute toxicity, and was much more potent than the neuraminidase inhibitor oseltamivir carboxylate in vivo. Combined application of the LPGSA and oseltamivir carboxylate revealed a synergistic inhibitory effect and successfully prevented influenza virus infection in mice. (C) 2017 Elsevier Ltd. All rights reserved.