Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

中文翻译：

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流感病毒聚合酶复合物：结构，功能和抗病毒药物设计意义的更新。

流感病毒会导致季节性流行病和大流行病爆发，与高发病率和高死亡率相关，并造成巨大损失。由于对现有抗流感药物的耐药性正在上升，因此迫切需要具有不同作用方式的创新抑制剂。流感病毒聚合酶复合物在甲型流感病毒（人源或人畜共患病）和乙型流感病毒的病毒复制和高度保护中起着关键作用，因此被广泛认为是关键药物靶标。我们在这里回顾了近年来在阐明该蛋白复合物的结构和功能，使结构辅助药物设计朝PA核酸内切酶，PB1聚合酶或结合帽的PB2亚基的核心区域发展方面所取得的重大进展。另外，抑制剂可能靶向蛋白质-蛋白质相互作用位点，与病毒RNA合成有关的细胞因子，病毒RNA本身或病毒核糖核蛋白的核蛋白成分。针对这些多种药理学目标的最新进展，除了在开发的各个阶段都使用了几种实验性抑制剂外，还在晚期（例如，favipiravir和VX-787）或早期临床试验中产生了药物。