Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• antivirals
• cap-binding domain
• endonuclease domain
• neuraminidase and matrix 2 inhibitors
• nucleoprotein inhibitors
• replication and transcription
• resistance
• ribonucleoprotein complex

Declaration of interest

The authors are funded by the Agence Nationale de la Recherche, FLUNUCLEOVIR ANR 2010 Blan-130701 and RNAP-IAV ANR Blanc -14-CE09-0017. This work was granted access to the HPC resources of IDRIS made by Grand Equipment National de Calcul Intensif under the grant 2012-076378 attributed. This work used the platforms of the Grenoble Instruct Center (Integrated Structural Biology Grenoble; UMS3518 CNRS-CEA-UJF-EMBL) with support from The French Infrastructure for Integrated Structural Biology (ANR-10-INSB-05-02) and The Alliance Grenobloise pour la Biologie Structurale et Cellulaire Intégrées (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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