tetano
Editor, Senior Moderator
Sci Rep. 2016 Aug 11;6:31500. doi: 10.1038/srep31500.
[h=1]N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.[/h] Carcelli M[SUP]1[/SUP], Rogolino D[SUP]1[/SUP], Gatti A[SUP]1[/SUP], De Luca L[SUP]2[/SUP], Sechi M[SUP]3[/SUP], Kumar G[SUP]4[/SUP], White SW[SUP]4[/SUP], Stevaert A[SUP]5[/SUP], Naesens L[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics. This is an enzyme with divalent metal ion(s) (Mg(2+) or Mn(2+)) in its catalytic site: chelation of these metal cofactors is an attractive strategy to inhibit enzymatic activity. Here we report the activity of a series of N-acylhydrazones in an enzymatic assay with PA-Nter endonuclease, as well as in cell-based influenza vRNP reconstitution and virus yield assays. Several N-acylhydrazones were found to have promising anti-influenza activity in the low micromolar concentration range and good selectivity. Computational docking studies are carried on to investigate the key features that determine inhibition of the endonuclease enzyme by N-acylhydrazones. Moreover, we here describe the crystal structure of PA-Nter in complex with one of the most active inhibitors, revealing its interactions within the protein's active site.
PMID: 27510745 DOI: 10.1038/srep31500
[PubMed - in process]
[h=1]N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.[/h] Carcelli M[SUP]1[/SUP], Rogolino D[SUP]1[/SUP], Gatti A[SUP]1[/SUP], De Luca L[SUP]2[/SUP], Sechi M[SUP]3[/SUP], Kumar G[SUP]4[/SUP], White SW[SUP]4[/SUP], Stevaert A[SUP]5[/SUP], Naesens L[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics. This is an enzyme with divalent metal ion(s) (Mg(2+) or Mn(2+)) in its catalytic site: chelation of these metal cofactors is an attractive strategy to inhibit enzymatic activity. Here we report the activity of a series of N-acylhydrazones in an enzymatic assay with PA-Nter endonuclease, as well as in cell-based influenza vRNP reconstitution and virus yield assays. Several N-acylhydrazones were found to have promising anti-influenza activity in the low micromolar concentration range and good selectivity. Computational docking studies are carried on to investigate the key features that determine inhibition of the endonuclease enzyme by N-acylhydrazones. Moreover, we here describe the crystal structure of PA-Nter in complex with one of the most active inhibitors, revealing its interactions within the protein's active site.
PMID: 27510745 DOI: 10.1038/srep31500
[PubMed - in process]