tetano
Editor, Senior Moderator
ACS Med Chem Lett. 2015 Jun 18;6(8):866-71. doi: 10.1021/acsmedchemlett.5b00109. eCollection 2015.
[h=1]Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors.[/h] Pala N[SUP]1[/SUP], Stevaert A[SUP]2[/SUP], Dallocchio R[SUP]3[/SUP], Dess? A[SUP]3[/SUP], Rogolino D[SUP]4[/SUP], Carcelli M[SUP]4[/SUP], Sanna V[SUP]1[/SUP], Sechi M[SUP]1[/SUP], Naesens L[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Influenza virus PA endonuclease; PA inhibitors (PAIs); dihydroxy-1H-indole-2-carboxamides; metal chelation; pharmacophore−structure virtual screening; polymerase
PMID: 26288686 [PubMed] PMCID: PMC4538433 [Available on 2016-08-13]
[h=1]Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors.[/h] Pala N[SUP]1[/SUP], Stevaert A[SUP]2[/SUP], Dallocchio R[SUP]3[/SUP], Dess? A[SUP]3[/SUP], Rogolino D[SUP]4[/SUP], Carcelli M[SUP]4[/SUP], Sanna V[SUP]1[/SUP], Sechi M[SUP]1[/SUP], Naesens L[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Influenza virus PA endonuclease; PA inhibitors (PAIs); dihydroxy-1H-indole-2-carboxamides; metal chelation; pharmacophore−structure virtual screening; polymerase
PMID: 26288686 [PubMed] PMCID: PMC4538433 [Available on 2016-08-13]