Influenza Virus Nucleoprotein: Structure, RNA Binding, Oligomerization and Antiviral Drug Target

Abstract

The nucleoprotein (NP) of influenza virus covers the viral RNA entirely and it is this NP–RNA complex that is the template for transcription and replication by the viral polymerase. Purified NP forms a dynamic equilibrium between monomers and small oligomers, but only the monomers can oligomerize onto RNA. Therefore, drugs that stabilize the monomers or that induce abnormal oligomerization may have an antiviral effect, as would drugs that interfere with RNA binding. Crystal structures have been produced for monomeric and dimeric mutants, and for trimers and tetramers; high-resolution electron microscopy structures have also been calculated for the viral NP–RNA complex. We explain how these structures and the dynamic oligomerization equilibrium of NP can be and have been used for anti-influenza drug development.

Keywords:

• antiviral
• nucleoprotein
• resistance
• RNP
• viral RNA

Financial & competing interests disclosure

This work was supported by the French agency for research (ANR; Flunucleovir; ANR-2010-Blanc-1307-1301 to A Slama-Schwok and RWH Ruigrok), MEDICEN and Lyonbiopole, the European Commission under grant agreement no. 259751 (Flupharm: New drugs targeting influenza virus polymerase, 11/2010-2005/2014 to RWH Ruigrok) and by a grant of the Programme de Recherche Influenza A (H1N1), coordinated by the Institut de Microbiologie et Maladies Infectieuses of the Institut National de la Santé et de la Recherche Médicale, INSERM, France (to B Delmas). 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.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the French agency for research (ANR; Flunucleovir; ANR-2010-Blanc-1307-1301 to A Slama-Schwok and RWH Ruigrok), MEDICEN and Lyonbiopole, the European Commission under grant agreement no. 259751 (Flupharm: New drugs targeting influenza virus polymerase, 11/2010-2005/2014 to RWH Ruigrok) and by a grant of the Programme de Recherche Influenza A (H1N1), coordinated by the Institut de Microbiologie et Maladies Infectieuses of the Institut National de la Santé et de la Recherche Médicale, INSERM, France (to B Delmas). 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. No writing assistance was utilized in the production of this manuscript.