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.

N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes / Carcelli, Mauro; Rogolino, Dominga; Gatti, Anna; De Luca, Laura; Sechi, Mario; Kumar, Gyanendra; White, Stephen W.; Stevaert, Annelies; Naesens, Lieve. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6:(2016), p. 31500. [10.1038/srep31500]

N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes

DE LUCA, Laura Maria;SECHI, Mario;
2016

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.
N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes / Carcelli, Mauro; Rogolino, Dominga; Gatti, Anna; De Luca, Laura; Sechi, Mario; Kumar, Gyanendra; White, Stephen W.; Stevaert, Annelies; Naesens, Lieve. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6:(2016), p. 31500. [10.1038/srep31500]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/168210
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