Flu channel drug resistance: a tale of two sites

Pielak, Rafal M.; Chou, James J.

doi:10.1007/s13238-010-0025-y

Cited by 73 publications

(62 citation statements)

References 53 publications

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“…Therefore, we determined the susceptibility of avian H2N2 viruses to two FDA-approved classes of influenza antivirals: the adamantanes and neuraminidase inhibitors (NAIs). Genetic resistance to adamantanes is conferred by combinations of M2 protein mutations at positions 26, 27, 30, 31, or 34 (39). All viruses tested in this study possess consensus M2 gene sequences that suggest genetic susceptibility to the adamantanes (Table 6).…”

Section: Resultsmentioning

confidence: 96%

Risk Assessment of H2N2 Influenza Viruses from the Avian Reservoir

Baranovich

Marathe

et al. 2014

J Virol

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H2N2 influenza A viruses were the cause of the 1957-1958 pandemic. Historical evidence demonstrates they arose from avian virus ancestors, and while the H2N2 subtype has disappeared from humans, it persists in wild and domestic birds. Reemergence of H2N2 in humans is a significant threat due to the absence of humoral immunity in individuals under the age of 50. Thus, examination of these viruses, particularly those from the avian reservoir, must be addressed through surveillance, characterization, and antiviral testing. The data presented here are a risk assessment of 22 avian H2N2 viruses isolated from wild and domestic birds over 6 decades. Our data show that they have a low rate of genetic and antigenic evolution and remained similar to isolates circulating near the time of the pandemic. Most isolates replicated in mice and human bronchial epithelial cells, but replication in swine tissues was low or absent. Multiple isolates replicated in ferrets, and 3 viruses were transmitted to direct-contact cage mates. Markers of mammalian adaptation in hemagglutinin (HA) and PB2 proteins were absent from all isolates, and they retained a preference for avian-like ␣2,3-linked sialic acid receptors. Most isolates remained antigenically similar to pandemic A/Singapore/1/57 (H2N2) virus, suggesting they could be controlled by the pandemic vaccine candidate. All viruses were susceptible to neuraminidase inhibitors and adamantanes. Nonetheless, the sustained pathogenicity of avian H2N2 viruses in multiple mammalian models elevates their risk potential for human infections and stresses the need for continual surveillance as a component of prepandemic planning.

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Section: Resultsmentioning

confidence: 96%

Risk Assessment of H2N2 Influenza Viruses from the Avian Reservoir

Baranovich

Marathe

et al. 2014

J Virol

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“…The fact that the omeprazole binds two sites in the molecule of the M2 protein could make the mechanism of action of this compound less sensitive to variations of the M2 protein, which as is known, have led to the emergence of many strains of influenza virus resistant against amantadanes (Sheu et al, 2011;Pielak and Chou, 2010).…”

Section: Resultsmentioning

confidence: 99%

Docking and Molecular Dynamics (MD) Simulations in Potential Drugs Discovery: An Application to Influenza Virus M2 Protein

Bozdaganyan¹,

Orekhov²,

Bragazzi³

et al. 2014

American Journal of Biochemistry and Biotechnology

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Molecular docking is a common method for searching new potential drugs. Improvement of the results of docking can be achieved by different ways-one of them is molecular dynamics simulations of protein-ligand complexes. As a model for our research we chose M2 membrane protein from influenza virus. M2 protein is a high selective tetrameric pH-gated proton channel. It was previously shown that Omeprazole Family Compounds (OFC) block the "proton pump", though we hypothesized further that they could interfere with the mechanism of fusion of the virus envelope and endosomal membrane, thereby hindering the M2 proton pump mechanism of influenza viruses. We carried out a Molecular Dynamics (MD) simulation in order to predict constant of binding for OFC. We simulated M2 Protein (PDB code 3C9J) in complex with its ligands: Amantadine, rimantadine as positive controls and omeprazole as putative ligand. We made use of molecular docking as well as the thermodynamic integration method to estimate binding free energies of the ligands. We demonstrate that the thermodynamic integration method predicts free energies of ligand binding better than molecular docking while embedding of M2 protein in a membrane further improves the calculated free energy values. Free energy calculations imply omeprazole as a potent anti-viral drug.

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“…Antiviral agents are an important part of a rational approach to epidemic influenza and are critical to prevent pandemic influenza, but the resistance of influenza to antiviral drugs is now widespread due to mutations in the influenza viruses [15]. Hence, development of new natural anti-influenza drugs becomes necessary and urgent.…”

Section: Chemicals and Standard Substancesmentioning

confidence: 99%

“…NA inhibitors are effective on both influenza A and B infections, and recommended by the WHO [14]. Nevertheless, the use of this class of antiviral drug has its limitations, such as drug-resistance, toxicity and cost [15][16][17][18]. Hence, new antiviral agents with high efficiency and low toxicity against the influenza virus are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Anti-Influenza Virus Activity and Constituents Characterization of Paeonia delavayi Extracts

Yang

Huang

2016

Molecules

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Paeonia delavayi, an endemic species in southwestern China, has been widely used as a traditional remedy for cardiovascular, extravasated blood, stagnated blood and female diseases in traditional Chinese medicine (TCM). However, there are no reports on the anti-influenza virus activity of this species. Here, the anti-influenza virus activity of P. delavayi root extracts was first evaluated by an influenza virus neuraminidase (NA) inhibition assay. Meantime, constituents in the active extracts were identified using ultra-high performance liquid coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and seven major identified constituents were used to further evaluate the NA inhibitory activity. The results showed that the ethyl acetate fraction (EA) and the ethanol fraction (E) of P. delavayi both presented strong NA inhibitory activity with IC 50 values of 75.932 µg/mL and 83.550 µg/mL, respectively. Twenty-seven constituents were characterized in these two active extracts by UPLC-Q-TOF-MS analysis, and seven major identified constituents exhibited high activity against the influenza virus.Among them, Benzoylpaeoniflorin (IC 50 = 143.701 µM) and pentagalloylglucose (IC 50 = 62.671 µM) exhibited the highest activity against the influenza virus, even far stronger than oseltamivir acid (IC 50 = 281.308 µM). This study indicated that P. delavayi was a strong NA inhibitor, but cell-based inhibition, anti-influenza virus activity in vivo and anti-influenza virus mechanism still need to be tested and explored.

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Flu channel drug resistance: a tale of two sites

Cited by 73 publications

References 53 publications

Risk Assessment of H2N2 Influenza Viruses from the Avian Reservoir

Risk Assessment of H2N2 Influenza Viruses from the Avian Reservoir

Docking and Molecular Dynamics (MD) Simulations in Potential Drugs Discovery: An Application to Influenza Virus M2 Protein

Anti-Influenza Virus Activity and Constituents Characterization of Paeonia delavayi Extracts

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