Charité-Universitätsmedizin Berlin, Institute of Virology, Berlin, Germany.
Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences (Research Centre of Biotechnology RAS), 33-2 Leninsky Prospect, 119071, Moscow, Russia.
Antiviral Res. 2022 Oct;206:105402. doi: 10.1016/j.antiviral.2022.105402. Epub 2022 Aug 23.
Regarding the problems with the current available drugs many research studies deal with the class of the dispirotripiperazine (DSTP)-based compounds. These are small molecules consisting of polycyclic saturated ring systems with positively charged nitrogen atoms. These compounds can interact with negatively charged HSPGs and thus block viral attachment. In a previous paper by Adfeldt et al. (2021), we have shown that the diazadispiroalkane derivatives 11826091 and 11826236 exhibit dose-dependent antiviral activity against human cytomegalovirus (HCMV) and pseudorabies virus (PrV). In the present study, these two small molecules are evaluated against two other herpesvirus species, murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1), as well as a HCMV clinical isolate. They exhibit potent antiherpetic activity against these herpesviruses with a high selectivity index. The low cytotoxicity was underlined by the LD determination in mice. We have shown that inhibition occurs at an early stage of infection. Interestingly, 11826091 and 11826236 reduced immediate early gene expression in HCMV and HSV-1 infected cells in a dose-dependent manner. Both small molecules probably interact electrostatically with sulfated glycosaminoglycans (GAGs) of proteoglycans on target cells resulting in blockage of adsorption sites for herpesvirus glycoprotein. Moreover, both compounds showed significant effects against the cell-associated viral spread of HSV-1 and HCMV. Overall, this study shows that 11826091 and 11826236 represent two promising candidates for a new approach of a broad antiviral therapy.
关于目前可用药物的问题，许多研究都涉及到双稠哌嗪（DSTP）类化合物。这些小分子由多环饱和环系统组成，带有正电荷的氮原子。这些化合物可以与带负电荷的 HSPGs 相互作用，从而阻止病毒附着。在 Adfeldt 等人之前的一篇论文中（2021 年），我们已经表明，二氮杂双稠烷衍生物 11826091 和 11826236 对人巨细胞病毒（HCMV）和伪狂犬病病毒（PrV）表现出剂量依赖性的抗病毒活性。在本研究中，这两种小分子针对另外两种疱疹病毒，即鼠巨细胞病毒（MCMV）和单纯疱疹病毒 1 型（HSV-1）以及 HCMV 临床分离株进行了评估。它们对这些疱疹病毒表现出强大的抗疱疹活性，具有很高的选择性指数。通过在小鼠中的 LD 测定强调了低细胞毒性。我们已经表明，抑制作用发生在感染的早期阶段。有趣的是，11826091 和 11826236 以剂量依赖性方式降低了 HCMV 和 HSV-1 感染细胞中即刻早期基因的表达。这两种小分子可能与靶细胞上的蛋白聚糖中的硫酸化糖胺聚糖（GAG）静电相互作用，导致疱疹病毒糖蛋白的吸附位点被阻断。此外，这两种化合物对 HSV-1 和 HCMV 的细胞相关病毒传播均表现出显著作用。总的来说，这项研究表明，11826091 和 11826236 是一种新的广谱抗病毒治疗方法的两个有前途的候选药物。
