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Tailor-made antiviral compounds: new anti-H1N1 and H3N2 influenza candidates identified

Based on in silico modelling, scientists of the Molecular Virology and Immunology Research Unit have demonstrated that of naproxen, a well-known anti-inflammatory agent has also newly discovered antiviral properties.  New naproxen derivatives has been designed for improved antiviral action by targeting the nucleoprotein NP of influenza A viruses

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Updated on 02/20/2014
Published on 02/20/2014

A few months ago (see article in March 2013), scientists in the Molecular Virology and Immunology Research Unit (INRA INSERM) working on the influenza A virus were able to accurately identify the site of interaction between the NP nucleoprotein and the RNA of the H1N1 virus.  This NP-RNA interaction is crucial to the formation of the RNP (ribo-nucleo-protein) system required for replication and multiplication of the influenza virus.  This identification was performed by modelling tools (3D representation in silico), based on the crystallographic structure of the NP protein. 

 The scientists searched compounds available in supplier catalogues able to interact within the specific site where viral NP binds RNA.  They identified naproxen - an anti-inflammatory agent that has been on the market for many years - as being able to bind into a key site of NP (a hydrophobic site formed by the amino acids Y148 and F489, flanked by R150 on one side and R361 and R355 on the other), thus inhibiting any interaction between this protein and the viral RNA.  This structural approach was validated by studies on H1N1 viruses carrying point mutations. These findings have been the subject of a patent filing (WO 2012143141).

Biological tests have then confirmed the antiviral properties of this drug.  Naproxen protected MDCK cells from viral challenges with H1N1 and H3N2, and exerted antiviral effects in mice.  Furthermore, the scientists did not observe the onset of any viral resistance to naproxen (a so-called escape phenomenon) after eight cell passages, as opposed to nucleozine (another novel antiviral candidate) that led to resistance mutations in the viruses after five cell passages.  These results thus showed that naproxen targets conserved residues that are vital to the virus, which is not the case of most antivirals.

The researchers are currently pursuing work on naproxen and its derivatives.  Based on computer modelling, and by grafting different chemical groups on the lead compound, they are targeting additional amino acids (around Y148) in order to enhance affinity for the NP, with derivatives having expected increased antiviral activity and improved therapeutic index. The scientists have thus developed a second generation of "tailor-made" antiviral compounds.

The researchers are now looking for industrial partners who could be interested by novel antiviral candidates and their applications in the medical and veterinary fields.  

Contact(s)
Scientific contact(s):

  • Anny SLAMA-SCHWOK (+33 (0)1 34 65 26 15 ) Molecular Virology and Immunology Research Unit, UR 892
Associated Division(s):
Animal Health
Associated Centre(s):
Jouy-en-Josas

For further information

  • Structure-based discovery of the novel antiviral properties of naproxen targeting the nucleoprotein of Influenza A virus. Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Ruigrok R, Delmas B, Di Primo C, Slama-Schwok A. Antimicrobial Agents and Chemotherapy 2013, 57(5): 2231-2242
  • Influenza virus nucleoprotein: structure, RNA binding, oligomerization and antiviral drug target. Chenavas S, Crépin T, Delmas B, Ruigrok R, Slama-Schwok A. Future Microbiology 2013, 8(12), 1537–1545
  • Monomeric nucleoprotein of Influenza A virus. Chenavas S, Estrozi LF, Slama-Schwok A, Delmas B, Di Primo C, Baudin F, Li X, Crépin T, Ruigrok RWH. Plos Pathogens 2013, 9(3): e1003275
  • Molecular dynamics studies of the nucleoprotein of influenza A virus: role of the protein flexibility in RNA binding. Tarus B, Chevalier C, Richard CA, Delmas B, Di Primo C, Slama-Schwok A. PLoS One. 2012, 7(1): e30038.
  • Oligomerization paths of the nucleoprotein of influenza A virus. Tarus B, Bakowiez O, Chenavas S, Duchemin L, Estrozi LF, Bourdieu C, Lejal N, Bernard J, Moudjou M, Chevalier C, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A. Biochimie 2012, 94(3):776-85.
  • “Antiviral compositions directed against the influenza virus nucleoprotein” Brevet WO 2012143141
  • Tailor-made antiviral compounds to combat influenza A.