690639-08-8Relevant academic research and scientific papers
Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors
Pala, Nicolino,Stevaert, Annelies,Dallocchio, Roberto,Dessì, Alessandro,Rogolino, Dominga,Carcelli, Mauro,Sanna, Vanna,Sechi, Mario,Naesens, Lieve
, p. 866 - 871 (2015)
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.
