Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University, Tübingen, Germany; Atriva Therapeutics GmbH, Christophstr. 32, 72072, Tübingen, Germany.
Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University, Tübingen, Germany; Atriva Therapeutics GmbH, Christophstr. 32, 72072, Tübingen, Germany; Virology Laboratory, Environmental Research Division, National Research Centre, Cairo, Egypt.
Antiviral Res. 2020 Jun;178:104806. doi: 10.1016/j.antiviral.2020.104806. Epub 2020 Apr 15.
Antiviral therapies against influenza are required, especially for high-risk patients, severe influenza and in case of highly pathogenic influenza virus (IV) strains. However, currently, licensed drugs that target the virus directly are not very effective and often lead to the development of resistant IV variants. This may be overcome by targeting host cell factors that are required for IV propagation. IV induces a variety of host cell signaling cascades, such as the Raf/MEK/ERK kinase pathway. The activation of this pathway is necessary for IV propagation. MEK-inhibitors block the activation of the pathway on the bottleneck of the signaling cascade leading to impaired virus propagation. In the present study, we aimed to compare the antiviral potency and bioavailability of the MEK-inhibitor CI-1040 versus its major active metabolite ATR-002, in vitro as well as in the mouse model. In cell culture assays, an approximately 10-fold higher concentration of ATR-002 is required to generate the same antiviral activity as for CI-1040. Interestingly, we observed that considerably lower concentrations of ATR-002 were required to achieve a reduction of the viral load in vivo. Pharmacokinetic studies with ATR-002 and CI-1040 in mice have found the C and AUC to be far higher for ATR-002 than for CI-1040. Our results thereby demonstrate the in vivo superiority of the active metabolite ATR-002 over CI-1040 as an antiviral agent despite its weaker cell membrane permeability. Therefore, ATR-002 is an attractive candidate for development as an efficient antiviral agent, especially given the fact that a treatment based on cellular pathway inhibition would be far less likely to lead to viral drug resistance.
需要针对流感的抗病毒疗法，特别是针对高危患者、重症流感和高致病性流感病毒（IV）株。然而，目前针对病毒的直接靶向药物效果并不理想，往往会导致 IV 变异株耐药性的产生。通过针对 IV 复制所需的宿主细胞因子进行靶向治疗可能会克服这一问题。IV 诱导多种宿主细胞信号级联反应，如 Raf/MEK/ERK 激酶途径。该途径的激活对于 IV 的复制是必需的。MEK 抑制剂在信号级联的瓶颈处阻断该途径的激活，从而导致病毒复制受损。在本研究中，我们旨在比较 MEK 抑制剂 CI-1040 及其主要活性代谢物 ATR-002 在体外和小鼠模型中的抗病毒效力和生物利用度。在细胞培养测定中，大约需要 10 倍浓度的 ATR-002 才能产生与 CI-1040 相同的抗病毒活性。有趣的是，我们观察到体内需要相当低的 ATR-002 浓度才能降低病毒载量。ATR-002 和 CI-1040 在小鼠中的药代动力学研究发现，ATR-002 的 C 和 AUC 远高于 CI-1040。我们的研究结果表明，尽管 ATR-002 的细胞膜通透性较弱，但作为抗病毒药物，其在体内的活性优于 CI-1040。因此，ATR-002 是一种很有吸引力的候选药物，可作为一种有效的抗病毒药物进行开发，特别是考虑到基于细胞途径抑制的治疗方法不太可能导致病毒耐药性。
