Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy
Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy
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DOI：
10.1093/jac/dkp161
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发表时间：
2009-07-01
影响因子：
5.2
通讯作者：
Ludwig, Stephan
中科院分区：
文献类型：
--
作者：
Ludwig, Stephan
流感仍然是世界范围内的主要瘟疫之一，有可能导致大流行。病毒对美国食品和药物管理局（FDA）批准的四种抗流感病毒药物的耐药性日益增加，这突出表明迫切需要为未来的流感流行或大流行准备新的抗病毒药物。虽然目前使用的抗病毒药物专门针对病毒因子，如神经氨酸酶或M2离子通道，但几种临床前方法现在专注于直接或间接与病毒复制相互作用的细胞因子或途径。其中，对病毒复制至关重要的细胞内信号级联的抑制剂已被解开作为最有前途的候选人。这篇短文的目的是突出这些新的方法，即，抑制经典的促有丝分裂Raf/MEK/ERK激酶级联和阻断导致转录因子NF-κ B激活的途径。已经表明，两种病毒诱导途径的抑制导致体外和体内病毒产生受损，而没有副作用或诱导抗性病毒变体的趋势。除了直接的抗病毒作用之外，此类抑制剂还可以通过阻断细胞因子爆发而发挥额外的有益作用，所述细胞因子爆发有助于高致病性流感病毒株引起的感染的严重性。尽管这些新策略仍处于临床前开发的早期阶段，但它们可能非常有前途，特别是在预防病毒耐药性方面。
Influenza is still one of the major plagues worldwide with the potential to cause pandemics. The increasing frequency of viral resistance to the four US Food and Drug Administration (FDA)-approved anti-influenza virus drugs underlines the urgent need for novel antivirals to be prepared for future influenza epidemics or pandemics. While the antivirals currently in use exclusively target viral factors, such as neuraminidase or the M2 ion channel, several pre-clinical approaches now focus on cellular factors or pathways that directly or indirectly interact with virus replication. Among these, inhibitors of intracellular signalling cascades that are essential for virus replication have been unravelled as the most promising candidates. This short article aims to highlight two of these novel approaches, namely, inhibition of the classical mitogenic Raf/MEK/ERK kinase cascade and blockade of the pathway that leads to activation of the transcription factor NF-kappa B. It has been shown that inhibition of both virus-induced pathways leads to impaired virus production in vitro and in vivo without side effects or the tendency to induce resistant virus variants. Besides the direct antiviral effect, such inhibitors may also exert additional beneficial effects by blocking the cytokine burst that contributes to the severity of infections by highly pathogenic influenza virus strains. Although these novel strategies are still in an early phase of pre-clinical development they might be very promising, especially with regard to prevention of viral resistance.