Influenza virus resistance to neuraminidase inhibitors

doi:10.1016/j.antiviral.2013.03.014

Antiviral Research

Volume 98, Issue 2, May 2013, Pages 174-185

https://doi.org/10.1016/j.antiviral.2013.03.014 Get rights and content

Highlights

•
The control of influenza infections remains a public health priority in the world.
•
Neuraminidase inhibitors (NAIS) have demonstrated significant clinical benefits.
•
The emergence of drug-resistant influenza variants constitutes a major concern.
•
The NA gene of resistant viruses may contain mutations that improve fitness and transmissibility.
•
There is a need for developing novel strategies by targeting host and other viral proteins.

Abstract

In addition to immunization programs, antiviral agents can play a major role for the control of seasonal influenza epidemics and may also provide prophylactic and therapeutic benefits during an eventual pandemic. The purpose of this article is to review the mechanism of action, pharmacokinetics and clinical indications of neuraminidase inhibitors (NAIs) with an emphasis on the emergence of antiviral drug resistance. There are two approved NAIs compounds in US: inhaled zanamivir and oral oseltamivir, which have been commercially available since 1999–2000. In addition, two other NAIs, peramivir (an intravenous cyclopentane derivative) and laninamivir (a long-acting NAI administered by a single nasal inhalation) have been approved in certain countries and are under clinical evaluations in others. As for other antivirals, the development and dissemination of drug resistance is a significant threat to the clinical utility of NAIs. The emergence and worldwide spread of oseltamivir-resistant seasonal A(H1N1) viruses during the 2007–2009 seasons emphasize the need for continuous monitoring of antiviral drug susceptibilities. Further research priorities should include a better understanding of the mechanisms of resistance to existing antivirals, the development of novel compounds which target viral or host proteins and the evaluation of combination therapies for improved treatment of severe influenza infections, particularly in immunocompromised individuals. This article forms part of a symposium in Antiviral Research on “Treatment of influenza: targeting the virus or the host.”

Introduction

Two classes of antiviral drugs are currently approved for the management of influenza infections: the adamantanes and the neuraminidase inhibitors (NAIs). The adamantane drugs or matrix (M)-2 blockers, amantadine and rimantadine, were developed in the 1960s and approved since then in many countries. Due to their activity against influenza A viruses only, their adverse effects, and the rapid emergence of resistance either during treatment or in the absence of drug pressure, the Centers for Disease Control and Prevention (CDC) has strongly advised against the use of this class of drugs (CDC, 2006). Hence, since 2010, the neuraminidase inhibitors are the only class of antivirals recommended by the WHO for the treatment and prophylaxis of influenza A and B infections (Pizzorno et al., 2011a).

Two NAIs are currently licensed worldwide for therapeutic and prophylactic uses: the oral agent oseltamivir phosphate, commercially available as Tamiflu (F. Hoffmann-La Roche) and the inhaled drug zanamivir, which is commercially available as Relenza (GlaxoSmithKline). During the 2009 influenza pandemic, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the parenteral drug peramivir (BioCryst) for the treatment of hospitalized patients with known or suspected influenza A(H1N1)pdm09 infection (Birnkrant and Cox, 2009). Peramivir is approved in Japan as Rapiacta and also available in South Korea as Peramiflu. Laninamivir octanoate (CS-8958), which is a prodrug of laninamivir (another inhaled NAI with long-acting properties), has also been approved in Japan and is commercially available under the name of Inavir (Daiichi Sankyo Company Ltd.). The latter two NAIs are currently in clinical evaluation in US and other countries. In this article, we review the mechanism of action, pharmacokinetics and clinical indications of NAIs with an emphasis on the emergence of antiviral drug resistance.

Section snippets

Mechanism of action of NAIs

Along with the hemagglutinin (HA), the neuraminidase (NA) is the other major influenza surface antigen. The latter is a mushroom-shaped homotetrameric glycoprotein with a stalk domain anchored to the viral membrane and a globular head that contains a catalytic site. While the HA protein is responsible for virus attachment to the sialic acid receptors on the host cell, the catalytic activity of the NA cleaves off the terminal N-acetyl neuraminic acid (Neu5Ac) on these 2,3 and 2,6 sialic acid

Structure, clinical indications and pharmacokinetics

Oseltamivir (GS4104) is an ethyl ester prodrug which requires ester hydrolysis to be converted to the active form oseltamivir carboxylate (GS4071). This compound was developed through modifications of the sialic acid analog framework, including the addition of a bulky lipophilic side chain, that allows the drug to be given orally (Kim et al., 1998) (Fig. 1). Like other NAIs, oseltamivir acts as a competitive inhibitor. Accordingly, it binds to the influenza viral NA active site and blocks the

Mechanisms of resistance

Influenza viruses with reduced sensitivity to NAI typically contain mutations in the NA which directly or indirectly alter the shape of the NA catalytic site, thus reducing the inhibitor binding ability. The catalytic site of the NA is constituted of eight functional residues (R-118, D-151, R-152, R-224, E-276, R-292, R-371, and Y-406), surrounded by eleven framework residues (E-119, R-156, W-178, S-179, D-198, I-222, E-227, H-274, E-277, N-294, and E-425) (N2 numbering system) implicated in

Management of NAI-resistant infections

In contrast to oseltamivir, resistance to zanamivir has remained infrequent among seasonal and pandemic influenza isolates to date. Due to structural differences between oseltamivir and zanamivir, influenza A variants containing the most frequent mutations conferring oseltamivir resistance (H274Y in the N1 subtype and E119V in the N2 subtype) were found to retain susceptibility to zanamivir (Gubareva, 2004, Pizzorno et al., 2011b). Accordingly, zanamivir is the antiviral of choice for the

Investigational agents and combination therapy

This review highlighted the increasing challenges of public health authorities and clinicians for the control of influenza infections during epidemics and occasional pandemics. It particularly emphasized the need to develop additional anti-influenza strategies to compensate for the inefficacy of adamantanes, for which influenza A(H1N1)pdm09 and A(H3N2) strains are resistant, and to address the issue of NAI-resistant variants that may emerge either during drug pressure or as a result of natural

Conclusion and perspectives

NAIs constitute an important tool for the control of influenza infections. Resistance to oseltamivir, the most prescribed NAI, has been found to occur not only during treatment and prophylaxis but also in the absence of NAI pressure. This observation was highlighted by the worldwide dissemination of the drug-resistant seasonal A(H1N1) H274Y variant during the 2007–2009 annual influenza epidemics. The detection of oseltamivir-resistant A(H1N1)pdm09 variants in untreated individuals and from a

References (149)

Y. Abed et al.
Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes
Antivir. Res.
(2008)
S. Bantia et al.
Anti-influenza virus activity of peramivir in mice with single intramuscular injection
Antivir. Res.
(2006)
E.Z. Baum et al.
A point mutation in influenza B confers resistance to peramivir and loss of slow binding
Antivir. Res.
(2003)
M. Baz et al.
Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir
Antivir. Res.
(2007)
D.A. Boltz et al.
Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice
Antivir. Res.
(2008)
J. Carr et al.
Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo
Antivir. Res.
(2002)
P.J. Collins et al.
Structural basis for oseltamivir resistance of influenza viruses
Vaccine
(2009)
K.C. Earhart et al.
Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt
J. Infect. Public Health
(2009)
O. Ferraris et al.
Sensitivity of influenza viruses to zanamivir and oseltamivir: a study performed on viruses circulating in France prior to the introduction of neuraminidase inhibitors in clinical practice
Antivir. Res.
(2005)
S. Fujisaki et al.
A single E105K mutation far from the active site of influenza B virus neuraminidase contributes to reducedsusceptibility to multiple neuraminidase-inhibitor drugs
Biochem. Biophys. Res. Commun.
(2012)

Y. Furuta et al.

T-705 (favipiravir) and related compounds: novel broad-spectrum inhibitors of RNA viral infections

Antivir. Res.

(2009)

L.V. Gubareva

Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors

Virus Res.

(2004)

A.C. Hurt et al.

Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives

Lancet Infect. Dis.

(2012)

A.C. Hurt et al.

Assessing the development of oseltamivir and zanamivir resistance in A(H5N1) influenza viruses using a ferret model

Antivir. Res.

(2010)

M. Kiso et al.

Resistant influenza A viruses in children treated with oseltamivir: descriptive study

Lancet

(2004)

J.L. McKimm-Breschkin

Resistance of influenza viruses to neuraminidase inhibitors-a review

Antivir. Res.

(2000)

Y. Abed et al.

Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds

Antivir. Ther.

(2006)

Y. Abed et al.

A novel neuraminidase deletion mutation conferring resistance to oseltamivir in clinical influenza A/H3N2 virus

J. Infect. Dis.

(2009)

Y. Abed et al.

Parenteral peramivir treatment for oseltamivir-resistant 2009 pandemic influenza A H1N1 viruses

J. Infect. Dis.

(2011)

Y. Abed et al.

Characterization of 2 influenza A(H3N2) clinical isolates with reduced susceptibility to neuraminidase inhibitors due to mutations in the hemagglutinin gene

J. Infect. Dis.

(2002)

Y. Abed et al.

A reverse genetics study of resistance to neuraminidase inhibitors in an influenza A/H1N1 virus

Antivir. Ther.

(2004)

Y. Abed et al.

Role of permissive neuraminidase mutations in influenza A/Brisbane/59/2007-like (H1N1) viruses

PLoS Pathog.

(2011)

F.Y. Aoki et al.

Influenza virus susceptibility and resistance to oseltamivir

Antivir. Ther.

(2007)

Y.S. Babu et al.

BCX-1812-a novel, highly potent, orally active and selective influenza neuraminidase inhibitor through structure-based drug design

J. Med. Chem.

(2000)

A.T. Baker et al.

Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus

Proteins

(1987)

S. Bantia et al.

Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir

Antimicrob. Agents Chemother.

(2001)

L. Barroso et al.

Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment

Antivir. Ther.

(2005)

M. Baz et al.

Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child

Clin. Infect. Dis.

(2006)

M. Baz et al.

Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis

N. Engl. J. Med.

(2009)

M. Baz et al.

Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses

J. Infect. Dis.

(2010)

Biota Holdings Ltd., 2009a. LANI Phase III clinical trials in Asia prove successful....

Biota Holdings Ltd., 2009b. Phase III trial with CS-8958 for flu prevention underway....

D. Birnkrant et al.

The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza

N. Engl. J. Med.

(2009)

J.D. Bloom et al.

Permissive secondary mutations enable the evolution of influenza oseltamivir resistance

Science

(2010)

J.D. Bloom et al.

A computational-experimental approach identifies mutations that enhance surface expression of an oseltamivir-resistant influenza neuraminidase

PLoS One

(2011)

B.J. Brennan et al.

Safety, tolerability and pharmacokinetics of intravenous oseltamivir: single and multiple dose phase I studies in healthy volunteers

Antimicrob. Agents Chemother.

(2012)

W.P. Burmeister et al.

The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid

EMBO J.

(1992)

D.P. Calfee et al.

Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection

Antimicrob. Agents Chemother.

(1999)

S. Carr et al.

Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer

Pediatr. Infect. Dis. J.

(2011)

L.M. Cass et al.

Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers

Clin. Pharmacokinet.

(1999)

CDC

High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents-United States, 2005–06 influenza season

MMWR Morb. Mortal. Wkly. Rep.

(2006)

CDC

Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis-North Carolina, 2009

MMWR Morb. Mortal. Wkly. Rep.

(2009)

CDC

Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients – Seattle, Washington, 2009

MMWR Morb. Mortal. Wkly. Rep.

(2009)

CDC

Update: influenza activity – United States, September 28, 2008–January 31, 2009

MMWR Morb. Mortal. Wkly. Rep.

(2009)

K. Chairat et al.

Pharmacokinetic properties of anti-influenza neuraminidase inhibitors

J. Clin. Pharmacol.

(2013)

L.F. Chen et al.

Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients-North Carolina, 2009

J. Infect. Dis.

(2011)

P.J. Collins et al.

Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants

Nature

(2008)

P.M. Colman et al.

Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase

J. Virol.

(1993)

P.M. Colman et al.

Structure of the catalytic and antigenic sites in influenza virus neuraminidase

Nature

(1983)

C. Dapat et al.

Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs

Emerg. Infect. Dis.

(2010)

Cited by (289)

Outlining recent updates on influenza therapeutics and vaccines: A comprehensive review
2024, Vaccine: X
Influenza virus has presented a considerable healthcare challenge during the past years, particularly in vulnerable groups with compromised immune systems. Therapeutics and vaccination have always been in research annals since the spread of influenza. Efforts have been going on to develop an antiviral therapeutic approach that could assist in better disease management and reduce the overall disease complexity, resistance development, and fatality rates. On the other hand, vaccination presents a chance for effective, long-term, cost-benefit, and preventive response against the morbidity and mortality associated with the influenza. However, the issues of resistance development, strain mutation, antigenic variability, and inability to cure wide-spectrum and large-scale strains of the virus by available vaccines remain there. The article gathers the updated data for the therapeutics and available influenza vaccines, their mechanism of action, shortcomings, and trials under clinical experimentation. A methodological approach has been adopted to identify the prospective therapeutics and available vaccines approved and within the clinical trials against the influenza virus. Review contains influenza therapeutics, including traditional and novel antiviral drugs and inhibitor therapies against influenza virus as well as research trials based on newer drug combinations and latest technologies such as nanotechnology and organic and plant-based natural products. Most recent development of influenza vaccine has been discussed including some updates on traditional vaccination protocols and discussion on next-generation and upgraded novel technologies. This review will help the readers to understand the righteous approach for dealing with influenza virus infection and for deducing futuristic approaches for novel therapeutic and vaccine trials against Influenza.
Anti-influenza virus activities and mechanism of antrafenine analogs
2023, European Journal of Medicinal Chemistry
Antrafenine is a drug initially designed for anti-inflammation uses. In this work we have synthesized a library of its structural analogs and tested the anti-influenza activities. These analogs belong to a group of 2-(quinolin-4-yl)amino benzamides or 2-(quinolin-4-yl)amino benzoate derivatives. Best performers were identified, namely 12, 34, 41, with IC₅₀ against A/WSN/33 (H1N1) of 5.53, 3.21 and 6.73 μM respectively. These chemicals were also effective against A/PR/8/34 (H1N1), A/HK/1/68 (H3N2) and B/Florida/04/2006 viruses. Time-of-addition study and minigenome luciferase reporter assay both supported that the compounds act on the ribonucleoprotein (RNP) components. Using 34 and 41 as representative compounds, we determined by microscale thermophoresis that this group of compounds bind to both PA C-terminal domain and the nucleoprotein (NP) which is the most abundant subunit of the RNP. Taken together, we have identified a new class of anti-influenza compounds with dual molecular targets and good potential to be further developed.
The influenza viruses, especially influenza A and B subtypes, cause many deaths each year. The high mutation rate of the virus renders available therapeutics less effective with time. In this work we identify a new class of compounds, structurally similar to the anti-inflammation drug antrafenine, with good potency against influenza A strains. The IC₅₀ of the best performers are within low micromolar range and thus have good potential for further development.
Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit
2023, European Journal of Medicinal Chemistry
The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-β³- or β^2,3 -amino acids were synthesized possessing a good binding affinity of PB2. The aza-β-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated. Then a lead HAA-09 was validated, and the attached aza-β³-amino acid moiety with acyclic tertiary carbon side chain well occupied in the key hydrophobic cavity of PB2_cap binding domain. Importantly, HAA-09 displays potent polymerase inhibition capacity, low cytotoxicity (selectivity index up to 2915) as well as robust anti-viral activity against A/WSN/33 (H1N1) virus and oseltamivir-resistant H275Y variant. Moreover, HAA-09 exhibited druggability with high plasma stability (t_1/2 ≥ 12 h) and no obvious hERG inhibition (IC₅₀ > 10 μM). Also, HAA-09 demonstrated a favorable safety profile when orally administrated in healthy mice at a high dose of 40 mg/kg QD for consecutive 3 days. Besides, in vivo therapeutic efficacy (85.7% survival observed at the day 15 post infection) was demonstrated when HAA-09 was administrated orally at 12.5 mg/kg BID starting 48 h post infection for 9 days. These data support that exploring the interactions between side chains on aza-β³- or β^2,3 -amino acid moieties and hydrophobic pocket of PB2_cap binding domain is a potential medicinal chemistry strategy for developing potent PB2 inhibitors.
Vitisin B inhibits influenza A virus replication by multi-targeting neuraminidase and virus-induced oxidative stress
2023, Acta Pharmaceutica Sinica B
Citation Excerpt :
NAIs prevent the release of progeny virions by interacting with the highly conserved active site of NA. However, a recent study demonstrated that H274Y, E119G/D/A, H274Y, and mutations of NA decrease virus susceptibility to NAIs, such as oseltamivir, zanamivir, and peramivir, resulting in a need for new antiviral agents9–19. Nevertheless, NA remains an attractive target for the development of anti-influenza drugs.
The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.
Enabling oral delivery of antiviral drugs: Double emulsion carriers to improve the intestinal absorption of zanamivir
2022, International Journal of Pharmaceutics
Citation Excerpt :
Moreover, the H275Y mutation has also been associated with resistance to peramivir, a hydrophilic neuraminidase inhibitor (clogP −1.37) that was approved for intravenous administration. Its classification as BCS class III (Table1) possibly accounts for the termination of the oral formulation development by Johnson & Johnson in 2001 (Samson et al. 2013). Laninamivir octanoate, a neuraminidase inhibitor currently approved for use only in Japan, is administered by inhalation, owing to its high solubility but low oral permeability properties (Table 1).
Antiviral drugs play a major role in the control of seasonal influenza epidemics and may provide prophylactic and therapeutic benefits during an eventual pandemic. Among the neuraminidase inhibitors, zanamivir has been shown to be a potent inhibitor of influenza viruses, and similarly against emerging resistant strains. Despite its high antiviral efficiency, zanamivir suffers from poor intestinal permeability, therefore administered via inhalation. Enabling oral delivery of zanamivir will augment the available antiviral tools in clinical practice, increase patient compliance and ultimately improve public health. Encapsulation of hydrophilic drugs within double emulsions (DEs), is an efficacious approach to enhance the oral bioavailability of BCS Class III drugs, such as zanamivir. The objective of this research was to increase the intestinal absorption of zanamivir by means of compatible DEs. Two different types of stable DEs were prepared comprising different internal aqueous phases (W₁). These micro-sized DEs showed high encapsulation efficacy (96.6–98.9 %) and markedly retarded the release rate of the antiviral drug. Both types of the zanamivir loaded DEs (zDEs) significantly increased the transport ability of zanamivir across a parallel artificial membrane. Furthermore, in-situ perfusion of zDEs revealed outstanding permeability of zanamivir across the intestinal wall of rats. The zDEs containing carbomer gel (rather than carboxymethyl cellulose) as W₁ obtained superior in-vivo effective permeability (P_eff); yet, both zDEs exhibited higher P_eff values (2–6-fold) than the low/high permeability marker (metoprolol). In conclusion, the DEs delivery system allowed overcoming the intestinal permeability barriers, towards successful oral administration of zanamivir.
The current strategies of optimization of oseltamivir against mutant neuraminidases of influenza A：A review
2022, European Journal of Medicinal Chemistry
Influenza with a tendency to cause pandemic and epidemic is an infectious disease with a high of morbidity and mortality. Neuraminidase (NA) inhibitors are proved to prevent and treat influenza. Among the four Neuraminidase inhibitors (NAIs) licensed, oseltamivir is most commonly used. With the extensive usage, several variants containing mutant NAs especially H274Y point mutation exhibit reduced susceptibility. In this review, we covered the current drugs available for influenza, the analysis of active site of NA, the mutant types of NAs and the molecular mechanism of drug resistance brought by H274Y mutant NAs. For recovering the susceptibility to oseltamivir, many series of oseltamivir analogues were designed. We present the details of the strategies of strengthening the interactions with S2 via introducing strong basic fragment, targeting additional subpockets and making full use of Zone X by modifying 3-pentyl of OC. PROTAC targeting NA and combination therapies are also introduced. Further, the advantages and disadvantages of these methods are also discussed.

View all citing articles on Scopus

¹: Authors contributed equally to this work.

View full text

ReviewInfluenza virus resistance to neuraminidase inhibitors

Highlights

Abstract

Introduction

Section snippets

Mechanism of action of NAIs

Structure, clinical indications and pharmacokinetics

Mechanisms of resistance

Management of NAI-resistant infections

Investigational agents and combination therapy

Conclusion and perspectives

Antivir. Res.

Antivir. Res.

Antivir. Res.

Antivir. Res.

Antivir. Res.

Antivir. Res.

Vaccine

J. Infect. Public Health

Antivir. Res.

Biochem. Biophys. Res. Commun.

Antivir. Res.

Virus Res.

Lancet Infect. Dis.

Antivir. Res.

Lancet

Antivir. Res.

Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds

Antivir. Ther.

A novel neuraminidase deletion mutation conferring resistance to oseltamivir in clinical influenza A/H3N2 virus

J. Infect. Dis.

Parenteral peramivir treatment for oseltamivir-resistant 2009 pandemic influenza A H1N1 viruses

J. Infect. Dis.

Characterization of 2 influenza A(H3N2) clinical isolates with reduced susceptibility to neuraminidase inhibitors due to mutations in the hemagglutinin gene

J. Infect. Dis.

A reverse genetics study of resistance to neuraminidase inhibitors in an influenza A/H1N1 virus

Antivir. Ther.

Role of permissive neuraminidase mutations in influenza A/Brisbane/59/2007-like (H1N1) viruses

PLoS Pathog.

Influenza virus susceptibility and resistance to oseltamivir

Antivir. Ther.

BCX-1812-a novel, highly potent, orally active and selective influenza neuraminidase inhibitor through structure-based drug design

J. Med. Chem.

Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus

Proteins

Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir

Antimicrob. Agents Chemother.

Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment

Antivir. Ther.

Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child

Clin. Infect. Dis.

Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis

N. Engl. J. Med.

Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses

J. Infect. Dis.

The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza

N. Engl. J. Med.

Permissive secondary mutations enable the evolution of influenza oseltamivir resistance

Science

A computational-experimental approach identifies mutations that enhance surface expression of an oseltamivir-resistant influenza neuraminidase

PLoS One

Safety, tolerability and pharmacokinetics of intravenous oseltamivir: single and multiple dose phase I studies in healthy volunteers

Antimicrob. Agents Chemother.

The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid

EMBO J.

Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection

Antimicrob. Agents Chemother.

Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer

Pediatr. Infect. Dis. J.

Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers

Clin. Pharmacokinet.

High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents-United States, 2005–06 influenza season

MMWR Morb. Mortal. Wkly. Rep.

Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis-North Carolina, 2009

MMWR Morb. Mortal. Wkly. Rep.

Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients – Seattle, Washington, 2009

MMWR Morb. Mortal. Wkly. Rep.

Update: influenza activity – United States, September 28, 2008–January 31, 2009

MMWR Morb. Mortal. Wkly. Rep.

Pharmacokinetic properties of anti-influenza neuraminidase inhibitors

Review
Influenza virus resistance to neuraminidase inhibitors