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

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

  • Bioorg Chem. 2021 Nov:116:105388. doi: 10.1016/j.bioorg.2021.105388.
Dominga Rogolino 1,  Lieve Naesens 2,  Jennifer Bartoli 3,  Mauro Carcelli 3,  Laura De Luca 4,  Giorgio Pelosi 3,  Ryjul W Stokes 5,  Ria Van Berwaer 6,  Serena Vittorio 4,  Annelies Stevaert 6,  Seth M Cohen 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, and CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici) Parma Unit, 43124 Parma, Italy. Electronic address: [email protected].
  • 2 Rega Institute for Medical Research, KU Leuven - University of Leuven, B-3000 Leuven, Belgium. Electronic address: [email protected].
  • 3 Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, and CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici) Parma Unit, 43124 Parma, Italy.
  • 4 Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Polo Universitario SS. Annunziata, Università di Messina, Viale Palatucci 13, Messina I-98168, Italy.
  • 5 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States.
  • 6 Rega Institute for Medical Research, KU Leuven - University of Leuven, B-3000 Leuven, Belgium.
PMID: 34670331 DOI: 10.1016/j.bioorg.2021.105388
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.

Keywords

Antiviral; Endonuclease; Influenza virus; Isoindolinone; Metal-binding pharmacophore.

Figures
Products