title: Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus.
abstract: The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function.
authors.affiliation: a Virologie et Immunologie Moléculaires, UR892, Institut National de la Recherche Agronomique , Domaine de Vilvert, 78350 Jouy en Josas , France.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tarus
authors.forename: Hélène
authors.initials: H
authors.lastname: Bertrand
authors.forename: Gloria
authors.initials: G
authors.lastname: Zedda
authors.forename: Carmelo
authors.initials: C
authors.lastname: Di Primo
authors.forename: Stéphane
authors.initials: S
authors.lastname: Quideau
authors.forename: Anny
authors.initials: A
authors.lastname: Slama-Schwok
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D006801:Humans; D009980:Influenza A virus / Q000737:chemistry* / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D056004:Molecular Dynamics Simulation; D009288:Naproxen / Q000031:analogs & derivatives / Q000737:chemistry* / Q000627:therapeutic use; D009698:Nucleoproteins / Q000737:chemistry*; D055503:Protein Multimerization; D012367:RNA, Viral / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D009698:Nucleoproteins; D012367:RNA, Viral; D009288:Naproxen
keywords: drug design; molecular modelling; nucleoprotein; oligomerization; viral RNA