Most viruses start their invasion by binding to glycoproteins’ moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPG-mimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses.

中文翻译：

---

具有烷基链的苯是多价杀病毒抗病毒药物的通用支架

大多数病毒通过与细胞表面的糖蛋白部分（硫酸乙酰肝素蛋白聚糖 [HSPG] 或唾液酸 [SA]）结合开始入侵。多价模仿这些部分的抗病毒药物被称为广谱多价进入抑制剂（MEI）。由于其可逆机制，当浓度低于抑制阈值时，功效就会丧失。为了克服这一限制，我们用疏水臂修饰 MEI，使抑制机制不可逆，即防止稀释时功效损失。然而，我们所有的 HSPG 模拟 MEIs 仅表现出对 HSPG 结合 SARS-CoV-2 的可逆抑制。在这里，我们对一系列小分子进行了系统研究，所有小分子都包含一个核心和多个以 HSPG 模拟部分封端的疏水臂。我们确定了对包括 SARS-CoV-2 在内的所有病毒具有不可逆抑制作用的病毒，并讨论了它们的设计原理。我们在治疗环境中（感染后 12 小时）通过鼻内滴注和气雾吸入在叙利亚仓鼠模型中显示了体内对抗 SARS-CoV-2 的功效。我们还展示了所提出的设计规则在生产 SA 模拟 MEI 中的实用性，并对 SA 结合流感病毒具有不可逆抑制作用。