Inhibition of the enhancement of infection of human immunodeficiency virus by semen-derived enhancer of virus infection using amyloid-targeting polymeric nanoparticles.
Inhibition of the enhancement of infection of human immunodeficiency virus by semen-derived enhancer of virus infection using amyloid-targeting polymeric nanoparticles.
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使用淀粉样蛋白靶向聚合物纳米颗粒，通过精液衍生的病毒感染增强剂来抑制人类免疫缺陷病毒的感染。
DOI：
10.1021/nn5067254
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发表时间：
2015-02-24
期刊：
影响因子：
17.1
通讯作者：
Yang, Jerry
中科院分区：
文献类型：
--
作者：
Sheik, Daniel A.;Brooks, Lauren;Frantzen, Kristen;Dewhurst, Stephen;Yang, Jerry
精液衍生的病毒感染增强剂（SEVI）是一种天然淀粉样物质，已被证明可以显著增加病毒在细胞中的附着和HIV的感染性。我们之前报道了合成的单聚和寡聚淀粉样蛋白靶向分子可以在SEVI上形成蛋白抗性涂层，并抑制SEVI和精液介导的HIV传染性增强。虽然与单体化合物相比，低聚淀粉样蛋白结合化合物与SEVI的表观结合有显著改善，但我们观察到与SEVI的表观结合与减少SEVI介导的HIV感染的活性之间只有适度的相关性。在这里，我们合成了淀粉样蛋白结合的聚丙烯酸酯基聚合物和大小与HIV病毒颗粒相当的聚合物纳米颗粒（~150 nm），以评估立体立体对抑制sevi介导的增强HIV传染性的影响。我们发现，这些聚合物材料在减少sevi介导的HIV感染增强方面表现出优异的能力，其中纳米颗粒的活性最高（IC50值为~4 μg/mL，或基于聚合物的59 nM），是迄今报道的任何sevi中和剂。结果表明，与靶向淀粉样蛋白的小分子相比，这些纳米材料的活性提高可能是由于它们的尺寸增加（直径= 80-200 nm），并且在抑制由SEVI淀粉样蛋白介导的病毒感染方面，空间相互作用可能发挥与结合亲和力同样重要的作用。与先前报道的SEVI中和淀粉样蛋白靶向分子（需要至少高于Kd 100倍的浓度才能观察到活性）相反，这些聚合物材料活性的表观Kd与IC50的比例约为1:1，这表明大多数与SEVI结合的聚合物分子有助于抑制SEVI增强的HIV感染。这种与尺寸有关的对蛋白质-蛋白质相互作用的物理抑制作用可能为靶向纳米材料在疾病干预中的应用提供进一步的机会。
The semen-derived enhancer of virus infection (SEVI) is natural amyloid material that has been shown to substantially increase viral attachment and infectivity of HIV in cells. We previously reported that synthetic monomeric and oligomeric amyloid-targeting molecules could form protein-resistive coatings on SEVI and inhibit SEVI- and semen-mediated enhancement of HIV infectivity. While oligomeric amyloid-binding compounds showed substantial improvement in apparent binding to SEVI compared to monomeric compounds, we observed only a modest correlation between apparent binding to SEVI and activity for reducing SEVI-mediated HIV infection. Here, we synthesized amyloid-binding polyacrylate-based polymers and polymeric nanoparticles of comparable size to HIV virus particles (~150 nm) to assess the effect of sterics on the inhibition of SEVI-mediated enhancement of HIV infectivity. We show that these polymeric materials exhibit excellent capability to reduce SEVI-mediated enhancement of HIV infection, with the nanoparticles exhibiting the greatest activity (IC50 value of ~4 μg/mL, or 59 nM based on polymer) of any SEVI-neutralizing agent reported to date. The results support that the improved activity of these nanomaterials is likely due to their increased size (diameters = 80-200 nm) compared to amyloid-targeting small molecules, and that steric interactions may play as important a role as binding affinity in inhibiting viral infection mediated by SEVI amyloids. In contrast to the previously reported SEVI neutralizing, amyloid-targeting molecules (which required concentrations at least 100-fold above the Kd to observe activity), the approximate 1:1 ratio of apparent Kd to IC50 for activity of these polymeric materials, suggests the majority of polymer molecules that are bound to SEVI contribute to the inhibition of HIV infectivity enhanced by SEVI. Such size-related effects on physical inhibition of protein-protein interactions may open further opportunities for the use of targeted nanomaterials in disease intervention.
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