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From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

Abstract : The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
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https://hal-amu.archives-ouvertes.fr/hal-02077007
Contributor : Annick Prémilleux <>
Submitted on : Friday, March 22, 2019 - 3:33:56 PM
Last modification on : Saturday, September 26, 2020 - 11:44:12 PM

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Sebastien Dilly, Aurelien Fotso Fotso, Nathalie Lejal, Gloria Zedda, Mohamad Chebbo, et al.. From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus. Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (16), pp.7202-7217. ⟨10.1021/acs.jmedchem.8b00557⟩. ⟨hal-02077007⟩

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