Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication.
Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication.
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DOI：
10.1099/jgv.0.001702
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Strang BL
中科院分区：
文献类型：
--
作者：
Falci Finardi N;Kim H;Hernandez LZ;Russell MRG;Ho CM;Sreenu VB;Wenham HA;Merritt A;Strang BL
当前抗人巨细胞病毒（HCMV）药物的缺点促使人们寻找具有新靶点的抗HCMV化合物。我们筛选了一系列生物活性化合物，并鉴定了一系列具有抑制 HCMV 复制潜力的化合物。在这些化合物中，我们选择了双苯甲亚胺化合物RO-90-7501进行进一步研究。我们生成了 RO-90-7501 的类似物，并发现一种化合物 MRT00210423 与 RO-90-7501 相比具有增强的抗 HCMV 活性。通过结合化合物类似物、显微镜检查和生化检测，我们发现 RO-90-7501 和 MRT00210423 与 DNA 相互作用。在单分子显微镜实验中，我们发现 RO-90-7501（而非 MRT00210423）能够压缩 DNA，这表明 DNA 压缩对于抗 HCMV 效果不是必需的。通过生物信息学分析，我们发现 HCMV DNA 基因组中存在许多假定的双苯甲亚胺结合位点。然而，使用蛋白质印迹、定量PCR和电子显微镜，我们发现在能够抑制HCMV复制的浓度下，我们的化合物对某些HCMV蛋白的产生或DNA合成影响很小或没有影响，但对HCMV衣壳产生具有显着的抑制作用。我们推断这些效应可能涉及我们的化合物与 HCMV 基因组和/或宿主细胞染色质的结合。因此，我们的数据扩展了我们对具有抗 HCMV 活性的化合物的理解，并表明双苯甲亚胺化合物靶向 DNA 可能是一种有用的抗 HCMV 策略。
The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.
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