Mechanistic investigation of the antiviral drug artesunate and its optimized synthetic derivatives

人巨细胞病毒感染是一个严重的，有时危及生命的医疗问题，特别是在免疫功能低下的个人和新生儿。标准更昔洛韦治疗的成功受到低药物相容性和诱导病毒耐药性的阻碍。一种新的策略是基于开发具有高口服生物利用度、药物安全性和无副作用的细胞定向信号传导抑制剂。青蒿琥酯是一种被批准的广谱抗感染药物，被认为是一种公认的治疗替代药物。在青蒿琥酯特异性抗病毒机制方面，我们证明了NF-κ B RelA/p65和NF-κ B依赖性信号通路的关键作用。然而，口服青蒿琥酯的治疗方法迄今为止还没有可靠的成功，部分原因是药物稳定性和代谢的变化。作为我们上一个项目期间的一个重要成果，可以合成新的青蒿琥酯衍生化合物，现在提供了比母体药物更大的优势。最近，我们证明了这些化学衍生物，包括二聚体，三聚体和杂合寡聚体，发挥显着增加的抗病毒功效和改善的药物稳定性。重要的是，目前的工作正在进行中，目的是在一个连接器为基础的固定这些衍生物用于目标捕捞实验。这些新的选择建议更新项目集中在三个问题上：（i）抗病毒活性的验证（基于siRNA的信号候选物的敲低），（ii）通过质谱分析鉴定药物靶点，（iii）在动物模型中评估广泛的抗疱疹病毒活性。这项研究将提供更深入的了解潜在的抗病毒机制，并可能导致青蒿琥酯和新的青蒿琥酯衍生的候选药物的药理潜力的优化。

Infection with the human cytomegalovirus is a serious, sometimes life-threatening medical problem, particularly in immunocompromised individuals and neonates. The success of standard ganciclovir 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 that possess high oral bioavailability, drug safety and lack of side-effects. Artesunate, an approved broad-spectrum antiinfective drug, is considered as a putative therapeutic alternative. In terms of the artesunate-specific antiviral mechanism, we demonstrated a key role of NF-kappaB RelA/p65 and the NF-kappaB-dependent signaling pathways. Therapeutic approaches with oral artesunate, however, have not been reliably successful so far, in part due to variable drug stability and metabolism. As an important outcome of our previous project period, novel artesunate-derived compounds could be synthesized, now offering substantial advantages over the parental drug. Recently, we demonstrated that these chemical derivatives, including dimers, trimers and hybrid oligomers, exert a markedly increased antiviral efficacy and improved drug stability. Importantly, current work is in progress aiming at a linker-based immobilization of these derivatives for use in target fishing experiments. These novel options suggest a renewal project focusing on three issues: (i) the validation of antiviral activity (siRNA-based knock-down of signaling candidates), (ii) drug target identification by mass spectrometry analyses and, (iii) an evaluation of broad antiherpesviral activity in animal models. This study will provide improved insights into the underlying antiviral mechanisms and may lead to an optimization of the pharmacological potential of artesunate and novel artesunate-derived drug candidates.