Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A(H1N1) Viruses: 2008–2010

Sheu, Tiffany G.; Fry, Alicia M.; Garten, Rebecca; Deyde, Varough; Shwe, Thein; Bullion, Lesley; Peebles, Patrick J.; Li, Yan; Klimov, Alexander; Gubareva, Larisa V.

doi:10.1093/infdis/jiq005

Cited by 116 publications

(118 citation statements)

References 16 publications

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“…We are not aware of similar findings elsewhere in the region, suggesting that the reassortment occurred while strains were cocirculating in Guangdong. This could also explain the sporadic findings by the NAI surveillance in Hong Kong (7,8,22). This subclade might have been therapy induced, considering the frequent use of adamantanes in China.…”

Section: Discussionmentioning

confidence: 89%

Adamantane- and Oseltamivir-Resistant Seasonal A (H1N1) and Pandemic A (H1N1) 2009 Influenza Viruses in Guangdong, China, during 2008 and 2009

et al. 2011

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Section: Discussionmentioning

confidence: 89%

Adamantane- and Oseltamivir-Resistant Seasonal A (H1N1) and Pandemic A (H1N1) 2009 Influenza Viruses in Guangdong, China, during 2008 and 2009

et al. 2011

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“…Furthermore, the small-molecule therapeutic space against influenza virus is currently limited to four licensed drugs: neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza), which prevent release of nascent virions (7), and amantadine (Symmetrel) and rimantadine (Flumadine), which are M2 ion channel inhibitors (8). However, the emergence of drug-resistant influenza variants has led to a decline in the efficacy of these drugs (9)(10)(11). Therefore, new influenza therapeutics with novel mechanisms of action and against new targets are urgently required to combat the persistent threat of influenza viruses.…”

mentioning

confidence: 99%

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Kadam

Wilson

2016

Proc. Natl. Acad. Sci. U.S.A.

387

359

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The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ∼16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter-and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.influenza virus | hemagglutinin | X-ray crystallography | Arbidol | fusion inhibitor

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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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Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A(H1N1) Viruses: 2008–2010

Cited by 116 publications

References 16 publications

Adamantane- and Oseltamivir-Resistant Seasonal A (H1N1) and Pandemic A (H1N1) 2009 Influenza Viruses in Guangdong, China, during 2008 and 2009

Adamantane- and Oseltamivir-Resistant Seasonal A (H1N1) and Pandemic A (H1N1) 2009 Influenza Viruses in Guangdong, China, during 2008 and 2009

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

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

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