tetano
Editor, Senior Moderator
Int J Mol Sci
. 2023 Jun 22;24(13):10495.
doi: 10.3390/ijms241310495. Identification of Anti-Influenza A Compounds Inhibiting the Viral Non-Structural Protein 1 (NS1) Using a Type I Interferon-Driven Screening Strategy
Giulia Marsili[SUP] 1 [/SUP], Chiara Acchioni[SUP] 1 [/SUP], Anna Lisa Remoli[SUP] 1 [/SUP], Donatella Amatore[SUP] 2 [/SUP], Rossella Sgarbanti[SUP] 2 [/SUP], Marta De Angelis[SUP] 2 3 [/SUP], Roberto Orsatti[SUP] 1 [/SUP], Marta Acchioni[SUP] 1 [/SUP], Andrea Astolfi[SUP] 4 [/SUP], Nunzio Iraci[SUP] 5 [/SUP], Simona Puzelli[SUP] 1 [/SUP], Marzia Facchini[SUP] 1 [/SUP], Edvige Perrotti[SUP] 1 [/SUP], Violetta Cecchetti[SUP] 4 [/SUP], Stefano Sabatini[SUP] 4 [/SUP], Fabiana Superti[SUP] 6 [/SUP], Mariangela Agamennone[SUP] 7 [/SUP], Maria Letizia Barreca[SUP] 4 [/SUP], John Hiscott[SUP] 8 [/SUP], Lucia Nencioni[SUP] 2 [/SUP], Marco Sgarbanti[SUP] 1 [/SUP]
Affiliations
There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164, were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.
Keywords: NS1; diverse compound library; influenza A viruses; luciferase reporter assay; pharmacophore modeling; small molecule screening; type I IFN.
. 2023 Jun 22;24(13):10495.
doi: 10.3390/ijms241310495. Identification of Anti-Influenza A Compounds Inhibiting the Viral Non-Structural Protein 1 (NS1) Using a Type I Interferon-Driven Screening Strategy
Giulia Marsili[SUP] 1 [/SUP], Chiara Acchioni[SUP] 1 [/SUP], Anna Lisa Remoli[SUP] 1 [/SUP], Donatella Amatore[SUP] 2 [/SUP], Rossella Sgarbanti[SUP] 2 [/SUP], Marta De Angelis[SUP] 2 3 [/SUP], Roberto Orsatti[SUP] 1 [/SUP], Marta Acchioni[SUP] 1 [/SUP], Andrea Astolfi[SUP] 4 [/SUP], Nunzio Iraci[SUP] 5 [/SUP], Simona Puzelli[SUP] 1 [/SUP], Marzia Facchini[SUP] 1 [/SUP], Edvige Perrotti[SUP] 1 [/SUP], Violetta Cecchetti[SUP] 4 [/SUP], Stefano Sabatini[SUP] 4 [/SUP], Fabiana Superti[SUP] 6 [/SUP], Mariangela Agamennone[SUP] 7 [/SUP], Maria Letizia Barreca[SUP] 4 [/SUP], John Hiscott[SUP] 8 [/SUP], Lucia Nencioni[SUP] 2 [/SUP], Marco Sgarbanti[SUP] 1 [/SUP]
Affiliations
- PMID: 37445672
- DOI: 10.3390/ijms241310495
There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164, were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.
Keywords: NS1; diverse compound library; influenza A viruses; luciferase reporter assay; pharmacophore modeling; small molecule screening; type I IFN.