title: Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza.
abstract: BACKGROUND
  Influenza viruses are a threat to human health. There are presently only two methods for treating influenza: vaccines, which require yearly updates, and two classes of antivirals that suffer with the problem of resistance by current human influenza viruses; this is especially the case with amantadine and rimantadine. Consequently, there is an urgent need for the development of new antivirals with new mechanisms of action.
  
  
  METHODS
  In this review, the authors focus on viral protein domains, their associated activity and their inhibition by small molecules defined by a structure-based design with a special emphasis on the ribonucleoprotein complex and its inhibitors. Several new classes of antiviral candidates targeting viral replication through individual domains of the polymerase and the nucleoprotein (NP) have been developed through structure-based design.
  
  
  CONCLUSIONS
  To date, the antivirals targeting neuraminidase are by far the most developed and potent. Antiviral candidates targeting the NP and polymerase domains are in the pipeline but their pharmacokinetics needs further studies. The recently published structures of the polymerase expand the possibilities for development of new antivirals. Combination therapies targeting conserved viral targets and new cellular proteins or exploiting drug promiscuity hold promises to fight against the emergence of resistance.
authors: University of Grenoble Alpes-EMBL-CNRS, Unit for Virus Host-Cell Interactions , 71 avenue des Martyrs, 38042 Grenoble , France.
authors: Alexandre
authors: A
authors: Monod
authors: Christopher
authors: C
authors: Swale
authors: Bogdan
authors: B
authors: Tarus
authors: Alice
authors: A
authors: Tissot
authors: Bernard
authors: B
authors: Delmas
authors: Rob Wh
authors: RW
authors: Ruigrok
authors: Thibaut
authors: T
authors: Crépin
authors: Anny
authors: A
authors: Slama-Schwok
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D024882:Drug Resistance, Viral; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012261:Ribonucleoproteins
keywords: antivirals; cap-binding domain; endonuclease domain; neuraminidase and matrix 2 inhibitors; nucleoprotein inhibitors; replication and transcription; resistance; ribonucleoprotein complex