Sulfoglycodendron Antivirals with Scalable Architectures and Activities,Journal of Chemical Information and Modeling

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Sulfoglycodendron Antivirals with Scalable Architectures and Activities
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jcim.4c00541
Francesco Coppola ₁ , Roya Jafari ₁ , Katherine D McReynolds ₂ , Petr Král _{1,

3}

Affiliation

Many viruses initiate their cell-entry by binding their multisubunit receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglycodendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multiprotein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed the detailed nature of binding between these antivirals and viral protein receptors and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

中文翻译：

具有可扩展架构和活性的磺基糖枝状抗病毒药物

许多病毒通过将其多亚基受体与人硫酸乙酰肝素蛋白聚糖（HSPG）和细胞膜上的其他分子成分结合来启动细胞进入。这些病毒相互作用可以被阻断，并且可以通过提供与病毒蛋白受体多价结合的合适 HSPG 模拟物来消除整个病毒。在这里，为此目的设计了不同拓扑、结构和大小的大型磺基糖枝状 HSPG 模拟物。原子分子动力学模拟用于检查这些广谱抗病毒药物阻断 HIV 、 SARS-CoV-2 、 HPV 和登革热病毒中多蛋白 HSPG 受体的能力。为了表征这些模拟物的抑制潜力，检查了它们与单个和多个蛋白质受体的结合。特别是，沿模拟轨迹引入和计算模拟物和病毒蛋白受体之间结合能的矢量分布。还进行了模拟受体结合的空间依赖性残留分析。该分析揭示了这些抗病毒药物和病毒蛋白受体之间结合的详细性质，并提供了证据，表明具有多价结合的大型抑制剂可能像分子胶一样在包膜病毒中启动蛋白质受体的自组装。

更新日期：2024-09-04

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