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

点击翻译按钮获取中文摘要

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.