Identification of a novel inhibitor of influenza virus polymerase based on inhibition of conformational change required for cap-dependent endonuclease activity

流感病毒聚合酶从细胞mRNAs中裂解带帽的RNA片段，并用作启动病毒转录的引物，从而产生带帽的病毒mRNA分子。这种独特的机制是发现抗流感疗法的目标。在这项研究中，我们研究了内切酶活性所需的该酶的构象变化，并基于对已鉴定的构象变化的抑制来筛选酶抑制剂。我们确定了显示帽子结合时构象变化的蛋白质区域和两个小化合物作为这种变化和帽子依赖的核酸内切酶活性的抑制物。

Influenza viral polymerase cleaves capped RNA fragments from cellular mRNAs and uses as primers for initiating viral transcription, which generates capped viral mRNA molecules. This unique mechanism is a target for the discovery of anti-influenza therapeutics. In this study, we investigated a conformational change of this enzyme required for the endonuclease activity, and screened enzymatic inhibitor based on inhibition of the identified conformational change. We identified the protein region showing the conformational change upon cap-binding and two small compounds as an inhibitor of both this change and cap-dependent endonuclease activity.