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

  • J Med Chem. 2018 Aug 23;61(16):7202-7217. doi: 10.1021/acs.jmedchem.8b00557.
Sébastien Dilly  1 ,  Aurélien Fotso Fotso  2 ,  Nathalie Lejal  3 ,  Gloria Zedda  4 ,  Mohamad Chebbo  2 ,  Fryad Rahman  2 ,  Simon Companys  4 ,  Hélène C Bertrand  4 ,  Jasmina Vidic  3 ,  Magali Noiray  5 ,  Marie-Christine Alessi  2 ,  Bogdan Tarus  3 ,  Stéphane Quideau  4 ,  Béatrice Riteau  2 ,  Anny Slama-Schwok  1  3
Affiliations
  • 1. Gustave Roussy Institute, Paris Saclay University, UMR8200 CNRS , 94805 Villejuif , France.
  • 2. Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France.
  • 3. Paris Saclay University, UR 892, INRA , 78352 Jouy en Josas , France.
  • 4. Bordeaux University, ISM (CNRS-UMR 5255) , 33405 Talence , France.
  • 5. Paris Sud University, Paris Saclay University, UMS IPSIT, Intermol , 92290 Châtenay-Malabry , France.
PMID: 30028133 DOI: 10.1021/acs.jmedchem.8b00557
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.