Identification of Anti-Influenza A Compounds Inhibiting the Viral Non-Structural Protein 1 (NS1) Using a Type I Interferon-Driven Screening Strategy
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Published:2023-06-22
Issue:13
Volume:24
Page:10495
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Marsili Giulia1ORCID, Acchioni Chiara1, Remoli Anna Lisa1, Amatore Donatella2, Sgarbanti Rossella2, De Angelis Marta23ORCID, Orsatti Roberto1, Acchioni Marta1, Astolfi Andrea4ORCID, Iraci Nunzio5ORCID, Puzelli Simona1, Facchini Marzia1, Perrotti Edvige1, Cecchetti Violetta4, Sabatini Stefano4ORCID, Superti Fabiana6ORCID, Agamennone Mariangela7ORCID, Barreca Maria Letizia4ORCID, Hiscott John8, Nencioni Lucia2ORCID, Sgarbanti Marco1ORCID
Affiliation:
1. Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy 2. Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy 3. Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy 4. Department of Pharmaceutical Sciences, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy 5. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy 6. National Centre for Innovative Technologies in Public Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy 7. Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy 8. Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy
Abstract
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.
Funder
Italian Ministry of Health, Istituto Superiore di Sanita’ 2010 Istituto Superiore di Sanità Sapienza Ateneo grants (LN) and EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases Italian Association for Cancer Research European Union’s Horizon 2020 research and innovation programme Marie Curie ITN INITIATE program
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference68 articles.
1. The influenza virus enigma;Salomon;Cell,2009 2. Simonsen, L., Spreeuwenberg, P., Lustig, R., Taylor, R.J., Fleming, D.M., Kroneman, M., Van Kerkhove, M.D., Mounts, A.W., Paget, W.J., and Teams, G.L.C. (2013). Global mortality estimates for the 2009 Influenza Pandemic from the GLaMOR project: A modeling study. PLoS Med., 10. 3. European Food Safety Authority, European Centre for Disease Prevention and Control, European Union Reference Laboratory for Avian Influenza, Adlhoch, C., Fusaro, A., Gonzales, J.L., Kuiken, T., Marangon, S., Niqueux, E., and Staubach, C. (2022). Avian influenza overview June–September 2022. EFSA J., 20, e07597. 4. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus;Claas;Lancet,1998 5. Human infection with a novel avian-origin influenza A (H7N9) virus;Gao;N. Engl. J. Med.,2013
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