[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of Influenza A virus
Nathalie Lejal 1, Bogdan Tarus 1, Edwige Bouguyon 1, Sylvie Chenavas 2, Nicolas Bertho 1, Bernard Delmas 1, Rob WH Ruigrok 2, Carmelo Di Primo 3 and Anny Slama-Schwok 1,#
Author Affiliations: 1Virologie et Immunologie Moléculaires, UR892, Institut National de la Recherche Agronomique, Domaine de Vilvert, 78350 Jouy en Josas, France 2Unit of Virus Host Cell Interactions UVHCI, UMI 3265 UJF-EMBL-CNRS, 6 rue Jules Horowitz, B.P. 181 38042 Grenoble cedex 9, France 3INSERM U869, Laboratoire ARNA, Université of Bordeaux, F33000, Bordeaux, France
The nucleoprotein (NP) binds the viral RNA genome and associates with the polymerase in a ribonucleoprotein complex (RNP) required for transcription and replication of Influenza A virus. NP has no cellular counterpart and NP sequence is highly conserved, which led at considering NP a hot target in the search for antivirals. We report here that monomeric nucleoprotein can be inhibited by a small molecule binding in its RNA binding groove, resulting in a novel antiviral against Influenza A virus. We identified by virtual screening, naproxen, an anti-inflammatory drug that targeted the nucleoprotein to inhibit NP-RNA association required for NP function. Further docking and MD simulations identified in the RNA groove two NP-naproxen complexes of similar interaction energy. The predicted naproxen binding sites were tested using the Y148A, R152A, R355A and R361A proteins carrying single point mutations. Surface plasmon resonance, fluorescence and other in vitro experiments supported that naproxen binds at a site identified by MD simulations and showed that naproxen competed with RNA binding to wt NP and protected active monomers of the nucleoprotein against proteolytic cleavage. Naproxen protected MDCK cells against viral challenges with the H1N1 and H3N2 viral strains and was much more effective than other cyclooxygenase inhibitors in decreasing MDCK cells viral titers. In a mouse model of intranasal infection, naproxen treatment decreased the viral titers of mice lungs. In conclusion, naproxen is a promising lead compound for novel antivirals against Influenza A virus that targets the nucleoprotein in its RNA binding groove.
# Correspondent footnote Email: Anny.Schwok@gmail.com
Copyright © 2013, American Society for Microbiology. All Rights Reserved.