Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses

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J Virol. 2020 Jan 15. pii: JVI.02149-19. doi: 10.1128/JVI.02149-19. [Epub ahead of print] Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses.

Park JG¹, ?vila-P?rez G¹, Nogales A^1,2, Blanco-Lobo P¹, de la Torre JC³, Mart?nez-Sobrido L⁴.
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Abstract

Influenza A (IAV) and B (IBV) viruses are highly contagious pathogens that cause fatal respiratory disease every year with a high economic impact. In addition, IAV can cause pandemic infections of great consequences when new viruses are introduced into humans. In this study we evaluated ten previously described compounds with antiviral activity against mammarenaviruses for their ability to inhibit IAV infection using our recently described bi-reporter influenza A/Puerto Rico/8/34 H1N1 (BIRFLU). Among the ten tested compounds, eight [antimycin A (AmA), brequinar (BRQ), 6-azauridine, azaribine, pyrazofurin (PF), AVN-944, mycophenolate mofetil (MMF) and mycophenolic acid (MPA)], but not obatoclax and Osu-03012, showed potent anti-influenza virus activity in post-treatment conditions (EC₅₀ = 3.80 nM to 1.73 μM, SI-MTT > 28.90 to 13,157.89). AmA, 6-azauridine, azaribine and PF also showed potent inhibitory effect in pre-treatment (EC₅₀ = 0.14 μM to 0.55 μM, SI-MTT = 70.12 to > 357.14) or co-treatment (EC₅₀ = 34.69 nM to 7.52 μM, SI-MTT = 5.24 to > 1,441.33) settings. All of the compounds tested inhibited viral genome replication and gene transcription and none of them affected host cellular RNA polymerase II activities. The antiviral activity of the eight identified compounds against BIRFLU was further confirmed with seasonal IAVs (A/California/04/2009 H1N1 and A/Wyoming/3/2003 H3N2) and an IBV (B/Brisbane/60/2008, Victoria lineage), demonstrating their broad-spectrum prophylactic and therapeutic activity against currently circulating influenza viruses in humans. Altogether, our results identified a new set of antiviral compounds for the potential treatment of influenza viral infections.IMPORTANCE Influenza viruses are highly contagious pathogens and cause a major threat to human health. Vaccination remains the most effective tool to protect humans against influenza infection. However, vaccination does not always guarantee complete protection against drifted or, more noticeable, shifted influenza viruses. Although Food and Drug Administration (FDA) drugs are approved for the treatment of influenza infections, resistant influenza viruses to current FDA antivirals have been reported and continue to emerge. Therefore, there is an urgent need to find novel antivirals for the treatment of influenza viral infections in humans, a search that could be expedited by repurposing currently approved drugs. In this study, we assessed the influenza antiviral activity of ten compounds previously shown to inhibit mammarenavirus infection. Among them, eight drugs showed antiviral activities, providing a new battery of drugs that could be used for the treatment of influenza infections.
Copyright ? 2020 American Society for Microbiology.


PMID: 31941776 DOI: 10.1128/JVI.02149-19