Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
Institute of Organic Chemistry I, Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
Antiviral Res. 2018 Apr;152:104-110. doi: 10.1016/j.antiviral.2018.02.013. Epub 2018 Feb 16.
Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC of 0.03 ± 0.00 μM, which even exceled the antiviral potency of TF27 (EC 0.04 ± 0.01 μM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 μM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.
人巨细胞病毒（HCMV）是一种主要的人类病原体，与严重的病理有关，如免疫功能低下个体和新生儿的危及生命的感染过程。目前，抗病毒治疗仍然受到现有药物相当大的毒性和病毒耐药性的诱导的限制。最近，我们和其他人报告了广谱抗感染药物青蒿琥酯在体外和体内非常有效的抗病毒活性。在这里，我们进一步研究了优化的类似物，包括属于这一非常有趣的实验药物（倍半萜/三氧化物）的单体、二聚体和三聚体衍生物，并将这些类似物与之前鉴定的三聚体青蒿琥酯化合物 TF27 进行了比较。我们可以证明，（i）在所研究的八种单体、二聚体和三聚体青蒿琥酯衍生物中，即 TF79、TF85、TF87、TF93.2.4、TF111、TF57a 和 TF57ab，在原代人成纤维细胞中表现出很强的抗 HCMV 活性，（ii）EC 值在低至亚微摩尔浓度范围内，表明抗病毒活性比最近描述的青蒿琥酯类似物更高，（iii）一种三聚体化合物 TF79，表现出非常有希望的 EC 值为 0.03±0.00 μM，甚至优于抗病毒活性的 TF27（EC 值为 0.04±0.01 μM），（iv）细胞毒性（定量测量乳酸脱氢酶释放）水平在 100 至 30 μM 之间较低，因此与抗病毒浓度不同，（v）蛋白质表达水平分析表明病毒蛋白表达受到强烈抑制，（vi）来自 NF-κB 报告细胞系统的数据强烈表明这些化合物具有相同的抗病毒机制。总之，我们对这些新化合物的数据强烈鼓励我们早期关于青蒿琥酯类似物的聚合和杂交的概念，为生成抗疱疹病毒药物提供了一个极好的平台。
