Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus–cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (∼190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

病毒感染每年造成数百万人死亡。可用的抗病毒药物具有病毒特异性，并且对有限数量的人类病原体具有活性。通过模仿硫酸乙酰肝素蛋白聚糖（HSPG）（一种高度保守的病毒附着配体（VALs）靶标），可以阻止病毒与细胞相互作用的第一步的广谱物质。可逆的结合机制阻止了它们用作药物，因为稀释后失去了抑制作用。已知的VAL由紧密堆积的重复单元组成，但上述物质仅能结合其中的几个。我们设计了具有类似于HSPG的长而灵活的接头的抗病毒纳米颗粒，从而使病毒与有效结合的结合力得以模拟，结合力强且与VAL重复单元多价结合，从而产生了力（〜190 pN）最终导致不可逆的病毒变形。杀病毒测定，电子显微镜图像和分子动力学模拟均支持所提出的机理。这些颗粒没有细胞毒性，并且在体外对单纯疱疹病毒（HSV），人乳头瘤病毒，呼吸道合胞病毒（RSV），登革热和慢病毒具有不可逆的纳米摩尔活性。它们在被HSV-2感染的人宫颈阴道组织培养物中具有离体活性，而在受RSV感染的小鼠中具有体内活性。