Hutterer Corina, Niemann Ina, Milbradt Jens, Fröhlich Tony, Reiter Christoph, Kadioglu Onat, Bahsi Hanife, Zeitträger Isabel, Wagner Sabrina, Einsiedel Jürgen, Gmeiner Peter, Vogel Nico, Wandinger Sebastian, Godl Klaus, Stamminger Thomas, Efferth Thomas, Tsogoeva Svetlana B, Marschall Manfred
Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
Institute of Organic Chemistry I, FAU, Erlangen, Germany.
Antiviral Res. 2015 Dec;124:101-9. doi: 10.1016/j.antiviral.2015.10.003. Epub 2015 Nov 4.
Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of standard antiviral therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy is based on the exploitation of cell-directed signaling inhibitors. The broad antiinfective drug artesunate (ART) offers additional therapeutic options such as oral bioavailability and low levels of toxic side-effects. Here, novel ART-derived compounds including dimers and trimers were synthesized showing further improvements over the parental drug. Antiviral activity and mechanistic aspects were determined leading to the following statements: (i) ART exerts antiviral activity towards human and animal herpesviruses, (ii) no induction of ART-resistant HCMV mutants occurred in vitro, (iii) chemically modified derivatives of ART showed strongly enhanced anti-HCMV efficacy, (iv) NF-κB reporter constructs, upregulated during HCMV replication, could be partially blocked by ART treatment, (v) ART activity analyzed in stable reporter cell clones indicated an inhibition of stimulated NF-κB but not CREB pathway, (vi) solid-phase immobilized ART was able to bind to NF-κB RelA/p65, and (vii) peptides within NF-κB RelA/p65 represent candidates of ART binding as analyzed by in silico docking and mass spectrometry. These novel findings open new prospects for the future medical use of ART and ART-related drug candidates.
人巨细胞病毒（HCMV）感染是一个严重的医学问题，尤其是在免疫功能低下的个体和新生儿中。标准抗病毒治疗的成功受到药物相容性低和病毒耐药性诱导的阻碍。一种新策略基于利用细胞定向信号抑制剂。广泛的抗感染药物青蒿琥酯（ART）提供了额外的治疗选择，如口服生物利用度和低水平的毒副作用。在此，合成了包括二聚体和三聚体在内的新型ART衍生化合物，显示出比母体药物有进一步的改进。确定了抗病毒活性和作用机制方面，得出以下结论：（i）ART对人和动物疱疹病毒具有抗病毒活性；（ii）体外未出现ART耐药的HCMV突变体；（iii）ART的化学修饰衍生物显示出显著增强的抗HCMV疗效；（iv）在HCMV复制过程中上调的NF-κB报告基因构建体可被ART治疗部分阻断；（v）在稳定的报告细胞克隆中分析的ART活性表明其抑制了刺激的NF-κB通路而非CREB通路；（vi）固相固定的ART能够与NF-κB RelA/p65结合；（vii）通过计算机对接和质谱分析，NF-κB RelA/p65内的肽段是ART结合的候选物。这些新发现为ART及相关候选药物的未来医学应用开辟了新前景。
