Pala Nicolino, Stevaert Annelies, Dallocchio Roberto, Dessì Alessandro, Rogolino Dominga, Carcelli Mauro, Sanna Vanna, Sechi Mario, Naesens Lieve
Dipartimento di Chimica e Farmacia, Università di Sassari , Via Vienna 2, 07100 Sassari, Italy.
Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
ACS Med Chem Lett. 2015 Jun 18;6(8):866-71. doi: 10.1021/acsmedchemlett.5b00109. eCollection 2015 Aug 13.
The influenza virus RNA-dependent RNA polymerase complex (RdRp), a heterotrimeric protein complex responsible for viral RNA transcription and replication, represents a primary target for antiviral drug development. One particularly attractive approach is interference with the endonucleolytic "cap-snatching" reaction by the RdRp subunit PA, more precisely by inhibiting its metal-dependent catalytic activity which resides in the N-terminal part of PA (PA-Nter). Almost all PA inhibitors (PAIs) thus far discovered bear pharmacophoric fragments with chelating motifs able to bind the bivalent metal ions in the catalytic core of PA-Nter. More recently, the availability of crystallographic structures of PA-Nter has enabled rational design of original PAIs with improved binding properties and antiviral potency. We here present a coupled pharmacophore/docking virtual screening approach that allowed us to identify PAIs with interesting inhibitory activity in a PA-Nter enzymatic assay. Moreover, antiviral activity in the low micromolar range was observed in cell-based influenza virus assays.
流感病毒RNA依赖的RNA聚合酶复合物（RdRp）是一种负责病毒RNA转录和复制的异源三聚体蛋白复合物，是抗病毒药物开发的主要靶点。一种特别有吸引力的方法是干扰RdRp亚基PA的核酸内切“抢帽”反应，更确切地说是通过抑制其位于PA N端部分（PA-Nter）的金属依赖性催化活性。迄今为止发现的几乎所有PA抑制剂（PAIs）都带有具有螯合基序的药效团片段，能够结合PA-Nter催化核心中的二价金属离子。最近，PA-Nter晶体结构的可得性使得能够合理设计具有改善结合特性和抗病毒效力的新型PAIs。我们在此提出一种结合药效团/对接的虚拟筛选方法，该方法使我们能够在PA-Nter酶分析中鉴定出具有有趣抑制活性的PAIs。此外，在基于细胞的流感病毒分析中观察到了低微摩尔范围内的抗病毒活性。
