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

Hu, Yanmei; Sneyd, Hannah; Dekant, Raphael; Wang, Junyang

doi:10.2174/1568026617666170224122508

Cited by 60 publications

(51 citation statements)

References 118 publications

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“…and stained with mouse anti-influenza NP antibody, rabbit anti-M1, and DAPI to determine the localization of the viral NP, M1 protein, and nucleus, respectively. Nucleozin, a known NP inhibitor, was included as a control [ 29 ]. It was found that nucleozin inhibited the nuclear entry of NP at both 4 and 6 h p.i.…”

Section: Resultsmentioning

confidence: 99%

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

Zhang

Musharrafieh

et al. 2017

IJMS

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Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu®) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir-resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics.

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Section: Resultsmentioning

confidence: 99%

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

Zhang

Musharrafieh

et al. 2017

IJMS

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“…The polymerase complex consists of polymerase basic 2 (PB2), PB1 and polymerase acidic (PA). NP is a major structural protein that binds vRNA and cRNA to form the template of replication and transcription, and also interacts with the PB1 and PB2 to facilitate polymerization of RNP complex (Portela and Digard, 2002; Gabriel et al, 2008; Hu et al, 2017). The interaction of viral RNP components with cellular factors may determine the host specificity of IAV.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein–Protein Interaction With NP

Wang

et al. 2019

Front. Microbiol.

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Influenza A virus (IAV) is a worldwide ongoing health threat causing diseases in both humans and animals. The interaction between IAV and host is a dynamic and evolving process that influences the pathogenicity and host specificity of the virus. TRIM14, a member of tripartite motif (TRIM) family, has been demonstrated to possess a strong capability of regulating type I interferon and NF-κB induction in host defense against viral infection. In this study, we found that TRIM14 could restrict the replication of IAV in a type I interferon and NF-κB independent manner. Mechanistically, different domains of TRIM14 could selectively interact with the viral nucleoprotein (NP), resulting in disparate influences on the RNP formation and viral replication. In particular, the PRYSPRY domain of TRIM14 exhibited a potent inhibitory activity on NP protein stability and IAV replication. On the contrary, the ΔS2 domain could rather antagonize the function of PRYSPRY domain and promote the IAV RNP formation by stabilizing NP. At the biochemical level, TRIM14-NP interaction could induce the K48-linked ubiquitination and proteasomal degradation of NP. Moreover, due to the rapid degradation of newly synthesized NP, TRIM14 could effectively block the translocation of NP from cytoplasm to nucleus thus further restrain the propagation of IAV in host cells. Taken together, our study has unraveled a previously unknown mechanism of TRIM14 mediated inhibition on RNP formation and influenza virus replication, and provides a new paradigm of complex and multifaceted host–pathogen interaction between ISG and viral protein.

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“…The overall high conservation of NP 406−419 is probably due to its functional importance in the NP protein. The region is localized into a flexible tail-loop (residues 402-428) which mediate the NP-NP oligomerization (29). In this region, positions like the R416 can be found which is critical for the functionality of the protein (29); therefore, this region is expected to be less permissive to mutations.…”

Section: Discussionmentioning

confidence: 99%

“…The region is localized into a flexible tail-loop (residues 402-428) which mediate the NP-NP oligomerization (29). In this region, positions like the R416 can be found which is critical for the functionality of the protein (29); therefore, this region is expected to be less permissive to mutations. Thus, region NP 406−419 can be considered an optimal candidate for vaccines research due to the presence of T cells epitopes and its high conservation.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Newly Conserved SLA-II Epitope in a Structural Protein of Swine Influenza Virus

et al. 2020

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Despite the role of pigs as a source of new Influenza A Virus viruses (IAV) potentially capable of initiating human pandemics, immune responses to swine influenza virus (SwIV) in pigs are not fully understood. Several SwIV epitopes presented by swine MHC (SLA) class I have been identified using different approaches either in outbred pigs or in Babraham large white inbred pigs, which are 85% identical by genome wide SNP analysis. On the other hand, some class II SLA epitopes were recently described in outbred pigs. In this work, Babraham large white inbred pigs were selected to identify SLA II epitopes from SwIV H1N1. PBMCs were screened for recognition of overlapping peptides covering the NP and M1 proteins from heterologous IAV H1N1 in IFNγ ELISPOT. A novel SLA class II restricted epitope was identified in NP from swine H1N1. This conserved novel epitope could be the base for further vaccine approaches against H1N1 in pigs.

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

Cited by 60 publications

References 118 publications

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein–Protein Interaction With NP

Identification of a Newly Conserved SLA-II Epitope in a Structural Protein of Swine Influenza Virus

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