Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors

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• 作者：Nicolino Pala ; Annelies Stevaert ; Roberto Dallocchio ; Alessandro Dess矛 ; Dominga Rogolino ; Mauro Carcelli ; Vanna Sanna ; Mario Sechi ; Lieve Naesens
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：866-871
• 全文大小：357K
• ISSN：1948-5875

文摘

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 鈥渃ap-snatching鈥?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.