Are R292K, E119V and I222L substitutions associated with antiviral resistance in all Influenza virus subtypes within group 2 neuraminidases (N3, N6, N7, and N9)?

ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain. IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.

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Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance

Current Medicinal Chemistry ◽

10.2174/0929867324666170920165926 ◽

2019 ◽

Vol 25 (38) ◽

pp. 5115-5127 ◽

Cited By ~ 13

Author(s):

Julianna Han ◽

Jasmine Perez ◽

Adam Schafer ◽

Han Cheng ◽

Norton Peet ◽

...

Keyword(s):

Influenza Virus ◽

Small Molecule ◽

Virus Disease ◽

The Elderly ◽

Significant Loss ◽

Influenza Viruses ◽

Antiviral Resistance ◽

Novel Therapeutics ◽

Seasonal Epidemics ◽

Small Molecule Therapeutics

Background: Influenza viruses cause severe upper respiratory illness in children and the elderly during seasonal epidemics. Influenza viruses from zoonotic reservoirs can also cause pandemics with significant loss of life in all age groups. Although vaccination is one of the most effective methods to protect against seasonal epidemics, seasonal vaccines vary in efficacy, can be ineffective in the elderly population, and do not provide protection against novel strains. Small molecule therapeutics are a critical part of our antiviral strategies to control influenza virus epidemics and pandemics as well as to ameliorate disease in elderly and immunocompromised individuals. Objective: This review aims to summarize the existing antiviral strategies for combating influenza viruses, the mechanisms of antiviral resistance for available drugs, and novel therapeutics currently in development. Methods: We systematically evaluated and synthesized the published scientific literature for mechanistic detail into therapeutic strategies against influenza viruses. Results: Current IAV strains have developed resistance to neuraminidase inhibitors and nearly complete resistance to M2 ion channel inhibitors, exacerbated by sub-therapeutic dosing used for treatment and chemoprophylaxis. New tactics include novel therapeutics targeting host components and combination therapy, which show potential for fighting influenza virus disease while minimizing viral resistance. Conclusion: Antiviral drugs are crucial for controlling influenza virus disease burden, but their efficacy is limited by human misuse and the capacity of influenza viruses to circumvent antiviral barriers. To relieve the public health hardship of influenza virus, emerging therapies must be selected for their capacity to impede not only influenza virus disease, but also the development of antiviral resistance.

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Impact on antiviral resistance of E119V, I222L and R292K substitutions in influenza A viruses bearing a group 2 neuraminidase (N2, N3, N6, N7 and N9)

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkw275 ◽

2016 ◽

Vol 71 (11) ◽

pp. 3036-3045 ◽

Cited By ~ 6

Author(s):

Alexandre Gaymard ◽

Aymeric Charles-Dufant ◽

Murielle Sabatier ◽

Jean-Claude Cortay ◽

Emilie Frobert ◽

...

Keyword(s):

Influenza A ◽

Antiviral Resistance ◽

Influenza A Viruses ◽

Group 2

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Mutation and Epistasis in Influenza Virus Evolution

Viruses ◽

10.3390/v10080407 ◽

2018 ◽

Vol 10 (8) ◽

pp. 407 ◽

Cited By ~ 26

Author(s):

Daniel Lyons ◽

Adam Lauring

Keyword(s):

Public Health ◽

Influenza Virus ◽

Vaccine Efficacy ◽

Rapid Evolution ◽

Evolutionary Process ◽

Virus Evolution ◽

Influenza Viruses ◽

Antiviral Resistance ◽

Epistatic Interactions ◽

Public Health Challenge

Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through mutation and reassortment. Because many new traits require multiple mutations and mutations are frequently combined by reassortment, epistatic interactions between mutations play an important role in influenza virus evolution. While mutation and epistasis are fundamental to the adaptability of influenza viruses, they also constrain the evolutionary process in important ways. Here, we review recent work on mutational effects and epistasis in influenza viruses.

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The antiviral resistance of influenza virus

Therapy ◽

10.2217/thy.11.79 ◽

2011 ◽

Vol 8 (6) ◽

pp. 741-762 ◽

Cited By ~ 3

Author(s):

Vanessa Escuret ◽

Olivier Ferraris ◽

Bruno Lina

Keyword(s):

Influenza Virus ◽

Antiviral Resistance

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A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801999115 ◽

2018 ◽

Vol 115 (16) ◽

pp. 4240-4245 ◽

Cited By ~ 12

Author(s):

Rameshwar U. Kadam ◽

Ian A. Wilson

Keyword(s):

Influenza Virus ◽

Small Molecule ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Influenza A ◽

Binding Mode ◽

Host Cells ◽

Viral Pathogen ◽

Group 2 ◽

Group 1

The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N-cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N-cyclohexyltaurine binds to the heart of the conserved HA RBS. N-cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N-cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.

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INFLUENZA VIRUS SURVEILLANCE BY THE INSTITUTO ADOLFO LUTZ, INFLUENZA SEASON 2014: ANTIVIRAL RESISTANCE

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652015000100016 ◽

2015 ◽

Vol 57 (1) ◽

pp. 92-92

Author(s):

Katia Corrêa de Oliveira Santos ◽

Daniela Bernardes Borges da Silva ◽

Margarete Aparecida Benega ◽

Renato de Sousa Paulino ◽

Elian Reis E Silva Jr ◽

...

Keyword(s):

Influenza Virus ◽

Influenza Season ◽

Antiviral Resistance ◽

Virus Surveillance

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The Discovery of the Antiviral Resistance GeneMx: A Story of Great Ideas, Great Failures, and Some Success

Annual Review of Virology ◽

10.1146/annurev-virology-092917-043525 ◽

2018 ◽

Vol 5 (1) ◽

pp. 33-51 ◽

Cited By ~ 8

Author(s):

Otto Haller ◽

Heinz Arnheiter ◽

Jovan Pavlovic ◽

Peter Staeheli

Keyword(s):

Influenza Virus ◽

Antiviral Resistance ◽

Innate Resistance ◽

Interferon Stimulated Genes ◽

Pure Chance ◽

New View

The discovery of the Mx gene–dependent, innate resistance of mice against influenza virus was a matter of pure chance. Although the subsequent analysis of this antiviral resistance was guided by straightforward logic, it nevertheless led us into many blind alleys and was full of surprising turns and twists. Unexpectedly, this research resulted in the identification of one of the first interferon-stimulated genes and provided a new view of interferon action. It also showed that in many species, MX proteins have activities against a broad range of viruses. To this day, Mx research continues to flourish and to provide insights into the never-ending battle between viruses and their hosts.

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A cholesterol consensus motif is required for efficient intracellular transport and raft association of a group 2 HA from influenza virus

Biochemical Journal ◽

10.1042/bj20141114 ◽

2015 ◽

Vol 465 (2) ◽

pp. 305-314 ◽

Cited By ~ 14

Author(s):

Maren de Vries ◽

Andreas Herrmann ◽

Michael Veit

Keyword(s):

Influenza Virus ◽

G Protein ◽

Intracellular Transport ◽

G Protein Coupled Receptors ◽

Transmembrane Region ◽

Consensus Motif ◽

Group 2 ◽

External Part ◽

G Protein Coupled

The external part of the transmembrane region of HA (haemagglutinin) of influenza virus contains a cholesterol consensus motif originally identified in G-protein-coupled receptors. Various mutations in this motif retard transport of HA through the Golgi and reduce raft association.

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