Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus–Cell Interface

To address the urgent need for new agents to reduce the global occurrence and spread of AIDS, we investigated the underlying hypothesis that antagonists of the HIV-1 envelope (Env) gp120 protein and the host-cell coreceptor (CoR) protein can be covalently joined into bifunctional synergistic combinations with improved antiviral capabilities. A synthetic protocol was established to covalently combine a CCR5 small-molecule antagonist and a gp120 peptide triazole antagonist to form the bifunctional chimera. Importantly, the chimeric inhibitor preserved the specific targeting properties of the two separate chimera components and, at the same time, exhibited low to subnanomolar potencies in inhibiting cell infection by different pseudoviruses, which were substantially greater than those of a noncovalent mixture of the individual components. The results demonstrate that targeting the virus–cell interface with a single molecule can result in improved potencies and also the introduction of new phenotypes to the chimeric inhibitor, such as the irreversible inactivation of HIV-1.

为应对全球艾滋病疫情蔓延的迫切需求，本研究针对以下假说开展探究：HIV-1包膜（Env）gp120蛋白与宿主细胞共受体（CoR）的拮抗剂可经共价结合构建双功能协同组合，以提升抗病毒活性。本研究建立了一套合成方案，将CCR5小分子拮抗剂与gp120肽三唑拮抗剂共价结合，制备得到双功能嵌合抑制剂。值得注意的是，该嵌合抑制剂保留了两个单独组分的特异性靶向特性，同时在抑制不同假病毒感染宿主细胞的实验中展现出低至亚纳摩尔级的活性，其效力显著优于单独组分的非共价混合物。研究结果证实，通过单分子靶向病毒-细胞界面，不仅可提升抑制剂的活性效力，还能为嵌合抑制剂赋予全新表型，例如实现HIV-1的不可逆失活。