Tweet
Sci Rep. 2016 Aug 11;6:31500. doi: 10.1038/srep31500.
N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.
Carcelli M1, Rogolino D1, Gatti A1, De Luca L2, Sechi M3, Kumar G4, White SW4, Stevaert A5, Naesens L5.
Author information
Abstract
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]
N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.
Carcelli M1, Rogolino D1, Gatti A1, De Luca L2, Sechi M3, Kumar G4, White SW4, Stevaert A5, Naesens L5.
Author information
Abstract
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]