Dataset Information

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target.

ABSTRACT: Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background. Such a feature creates a grand challenge in devising therapeutic intervention strategies to inhibit influenza virus replication, as a single agent might not be able to inhibit all influenza virus strains. Both classes of currently approved anti-influenza drugs have limitations: the M2 channel blockers amantadine and rimantadine are no longer recommended for use in the U.S. due to predominant drug resistance, and resistance to the neuraminidase inhibitor oseltamivir is continuously on the rise. In pursuing the next generation of antiviral drugs with broad-spectrum activity and higher genetic barrier of drug resistance, the influenza virus nucleoprotein (NP) stands out as a high-profile drug target. This review summarizes recent developments in designing inhibitors targeting influenza NP and their mechanisms of action.

SUBMITTER: Hu Y

PROVIDER: S-EPMC5967877 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target.

Hu Yanmei Y Sneyd Hannah H Dekant Raphael R Wang Jun J

Current topics in medicinal chemistry 20170101 20

Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that ...[more]

PMID: 28240183

Similar Datasets

Project description:Developing antiviral therapies for influenza A virus (IAV) infection is an ongoing process because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. The ideal strategy is to develop drugs that target well-conserved, functionally restricted, and unique surface structures without affecting host cell function. We recently identified the antiviral compound, RK424, by screening a library of 50,000 compounds using cell-based infection assays. RK424 showed potent antiviral activity against many different subtypes of IAV in vitro and partially protected mice from a lethal dose of A/WSN/1933 (H1N1) virus in vivo. Here, we show that RK424 inhibits viral ribonucleoprotein complex (vRNP) activity, causing the viral nucleoprotein (NP) to accumulate in the cell nucleus. In silico docking analysis revealed that RK424 bound to a small pocket in the viral NP. This pocket was surrounded by three functionally important domains: the RNA binding groove, the NP dimer interface, and nuclear export signal (NES) 3, indicating that it may be involved in the RNA binding, oligomerization, and nuclear export functions of NP. The accuracy of this binding model was confirmed in a NP-RK424 binding assay incorporating photo-cross-linked RK424 affinity beads and in a plaque assay evaluating the structure-activity relationship of RK424. Surface plasmon resonance (SPR) and pull-down assays showed that RK424 inhibited both the NP-RNA and NP-NP interactions, whereas size exclusion chromatography showed that RK424 disrupted viral RNA-induced NP oligomerization. In addition, in vitro nuclear export assays confirmed that RK424 inhibited nuclear export of NP. The amino acid residues comprising the NP pocket play a crucial role in viral replication and are highly conserved in more than 7,000 NP sequences from avian, human, and swine influenza viruses. Furthermore, we found that the NP pocket has a surface structure different from that of the pocket in host molecules. Taken together, these results describe a promising new approach to developing influenza virus drugs that target a novel pocket structure within NP.

Dataset Information

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target.

Publications

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets