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

Sebastien Dilly; Aurelien Fotso Fotso; Nathalie Lejal; Gloria Zedda; Mohamad Chebbo; Fryad Rahman; Simon Companys; Helene C. Bertrand; Jasmina Vidic; Magali Noiray; Marie-Christine Alessi; Bogdan Tarus; Stephane Quideau; Beatrice Riteau; Anny Slama-Schwok

doi:10.1021/acs.jmedchem.8b00557

Journal articles

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

Sebastien Dilly Aurelien Fotso Fotso ^{1, 2} Nathalie Lejal ³ Gloria Zedda Mohamad Chebbo Fryad Rahman ^{1, 2} Simon Companys ⁴ Helene C. Bertrand ⁵ Jasmina Vidic ³ Magali Noiray Marie-Christine Alessi ^{1, 2} Bogdan Tarus ³ Stephane Quideau ⁴ Beatrice Riteau ^{1, 2} Anny Slama-Schwok ^{3, 6}

1 NORT - Nutrition, obésité et risque thrombotique

2 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research

3 VIM (UR 0892) - Unité de recherche Virologie et Immunologie Moléculaires

4 ISM - Institut des Sciences Moléculaires

5 LBM UMR 7203 - Laboratoire des biomolécules

6 Université Paris-Saclay

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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Journal articles

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Life Sciences [q-bio]

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https://hal-amu.archives-ouvertes.fr/hal-02077007
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Submitted on : Friday, March 22, 2019 - 3:33:56 PM
Last modification on : Saturday, July 3, 2021 - 12:21:33 AM

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

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