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) (Mg2+ or Mn2+) 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.
Highlights
Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics
We report the biological activity of a series of N-acylhydrazones (Fig. 2), as determined in an enzymatic assay with PA-Nter endonuclease as well as in cell-based influenza viral ribonucleoprotein reconstitution and virus yield assays
26 was here considered, because it is an inhibitor of HIV RNase H38, another enzyme with two magnesium ions in its active site
Summary
In 18 and 19, the gallic moiety can be involved in the chelation of the metal cofactors (mode C, Fig. 4). Compound 12 was synthesized in order to confirm the crucial influence of the gallic moiety. Since the inhibitory activity of the N-acylhydrazones could be related to chelation of the divalent metal cofactor(s) in the influenza PA-Nter active site, we investigated the coordination properties of one model ligand (i.e. 19, H2L) towards Mg2+. Different reaction conditions were used (1:1 and 1:2 metal to ligand ratio, up to 4 equivalents of triethylamine), but in any case the same chemical species Mg(HL)2∙4H2O was recovered and conveniently characterized. The use of a coordinating solvent as d6-DMSO causes partial decoordination of the ligand, but the 1H-NMR spectrum in MeOD, instead, shows only the signals attributable to the complex. IC50 24 >500 >500 >500 67 >500 54 >500 34 68 45 >500 69 >500 8.9 454 482 83 >500 18 13 75 8.7 131 40 30 36 40 5.3 ND
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