scholarly journals Structure-based design of stabilized recombinant influenza neuraminidase tetramers

2021 ◽  
Author(s):  
Daniel Ellis ◽  
Julia Lederhofer ◽  
Oliver J Acton ◽  
Yaroslav Tsybovsky ◽  
Sally Kephart ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Influenza Virus ◽  
Protein Design ◽  
Protective Immunity ◽  
Drug Target ◽  
Antiviral Drug ◽  
Structure Stability ◽  
Protective Antibodies ◽  
Structural Principles ◽  
Influenza Virus Neuraminidase

Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across all non-bat subtypes adopt various tetrameric conformations, including a previously unreported 'open' state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We used homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the 'closed' state. In addition to improving thermal stability, conformational stabilization improved affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. The stabilized NA proteins can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, as well as a roadmap towards structure-based discovery of NA-directed therapeutics and vaccines.

scholarly journals A Dual Controllability Analysis of Influenza Virus-Host Protein-Protein Interaction Networks for Antiviral Drug Target Discovery

2018 ◽  
Author(s):  
Emily E. Ackerman ◽  
John F. Alcorn ◽  
Takeshi Hase ◽  
Jason E. Shoemaker
Keyword(s):  
Influenza Virus ◽  
Protein Interaction ◽  
Drug Target ◽  
Influenza A ◽  
Antiviral Drug ◽  
Host Factors ◽  
Host Protein ◽  
Drug Target Discovery ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Networks

ABSTRACTHost factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. This knowledge can be utilized to understand disease dynamics and isolate proteins for study as drug target candidates. Both topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets.ImportanceSeasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year, with a constant threat of pandemic infection. Even so, the FDA has only approved four treatments, two of which are unsuited for at risk groups such as children and those with breathing complications. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. Controllability analyses identify key regulating host factors of the infected cell’s progression, findings which are supported by biological context. These results are beneficial to future studies of influenza virus, both experimental and computational.

scholarly journals Phosphoproteomic-based kinase profiling early in influenza virus infection identifies GRK2 as antiviral drug target

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Emilio Yángüez ◽  
Annika Hunziker ◽  
Maria Pamela Dobay ◽  
Soner Yildiz ◽  
Simon Schading ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Drug Target ◽  
Antiviral Drug ◽  
Influenza Virus Infection

Influenza virus nucleoprotein: structure, RNA binding, oligomerization and antiviral drug target

2013 ◽  
Vol 8 (12) ◽  
pp. 1537-1545 ◽  
Author(s):  
Sylvie Chenavas ◽  
Thibaut Crépin ◽  
Bernard Delmas ◽  
Rob WH Ruigrok ◽  
Anny Slama-Schwok
Keyword(s):  
Influenza Virus ◽  
Drug Target ◽  
Rna Binding ◽  
Antiviral Drug

scholarly journals Broadly protective human antibodies that target the active site of influenza virus neuraminidase

Science ◽  
2019 ◽  
Vol 366 (6464) ◽  
pp. 499-504 ◽  
Author(s):  
Daniel Stadlbauer ◽  
Xueyong Zhu ◽  
Meagan McMahon ◽  
Jackson S. Turner ◽  
Teddy J. Wohlbold ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Active Site ◽  
Influenza A ◽  
Vaccine Development ◽  
Functional Characterization ◽  
B Virus ◽  
Protective Antibodies ◽  
Major Surface ◽  
Influenza Virus Neuraminidase

Better vaccines against influenza virus are urgently needed to provide broader protection against diverse strains, subtypes, and types. Such efforts are assisted by the identification of novel broadly neutralizing epitopes targeted by protective antibodies. Influenza vaccine development has largely focused on the hemagglutinin, but the other major surface antigen, the neuraminidase, has reemerged as a potential target for universal vaccines. We describe three human monoclonal antibodies isolated from an H3N2-infected donor that bind with exceptional breadth to multiple different influenza A and B virus neuraminidases. These antibodies neutralize the virus, mediate effector functions, are broadly protective in vivo, and inhibit neuraminidase activity by directly binding to the active site. Structural and functional characterization of these antibodies will inform the development of neuraminidase-based universal vaccines against influenza virus.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

Docking and 3D QSAR study of thiourea analogs as potent inhibitors of influenza virus neuraminidase

2010 ◽  
Vol 16 (12) ◽  
pp. 1809-1818 ◽  
Author(s):  
Jiaying Sun ◽  
Shaoxi Cai ◽  
Hu Mei ◽  
Jian Li ◽  
Ning Yan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
3D Qsar ◽  
Qsar Study ◽  
Influenza Virus Neuraminidase

scholarly journals Network-Guided Discovery of Influenza Virus Replication Host Factors

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Emily E. Ackerman ◽  
Eiryo Kawakami ◽  
Manami Katoh ◽  
Tokiko Watanabe ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Replication ◽  
Virus Replication ◽  
Drug Targets ◽  
Antiviral Drug ◽  
Viral Proteins ◽  
Host Factors ◽  
Ppi Network ◽  
Host Proteins ◽  
Influenza Virus Replication

ABSTRACTThe positions of host factors required for viral replication within a human protein-protein interaction (PPI) network can be exploited to identify drug targets that are robust to drug-mediated selective pressure. Host factors can physically interact with viral proteins, be a component of virus-regulated pathways (where proteins do not interact with viral proteins), or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining human PPI networks with virus-host PPI data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow, even after the removal of known abundance-degree bias within PPI data. We have isolated a subnetwork of the human PPI network that connects virus-interacting host proteins to host factors that are important for influenza virus replication without physically interacting with viral proteins. The subnetwork is enriched for signaling and immune processes distinct from those associated with virus-interacting proteins. Selecting proteins based on subnetwork topology, we performed an siRNA screen to determine whether the subnetwork was enriched for virus replication host factors and whether network position within the subnetwork offers an advantage in prioritization of drug targets to control influenza virus replication. We found that the subnetwork is highly enriched for target host proteins—more so than the set of host factors that physically interact with viral proteins. Our findings demonstrate that network positions are a powerful predictor to guide antiviral drug candidate prioritization.IMPORTANCEIntegrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.

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