Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15–17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors.

Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease / Rogolino, D.; Naesens, L.; Bartoli, J.; Carcelli, M.; De Luca, L.; Pelosi, G.; Stokes, R. W.; Van Berwaer, R.; Vittorio, S.; Stevaert, A.; Cohen, S. M.. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 116(2021), p. 105388.105388. [10.1016/j.bioorg.2021.105388]

Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease

Rogolino D.;Bartoli J.;Carcelli M.;Pelosi G.;
2021

Abstract

Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15–17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors.
Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease / Rogolino, D.; Naesens, L.; Bartoli, J.; Carcelli, M.; De Luca, L.; Pelosi, G.; Stokes, R. W.; Van Berwaer, R.; Vittorio, S.; Stevaert, A.; Cohen, S. M.. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 116(2021), p. 105388.105388. [10.1016/j.bioorg.2021.105388]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2901489
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