Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase

Ramírez-Salinas, G. Lizbeth; García-Machorro, Jazmín; Quiliano, Miguel; Zimic, Mirko; Briz, Verónica; Rojas-Hernández, Saúl; Correa‐Basurto, José

doi:10.1007/s00894-015-2835-6

Cited by 5 publications

(2 citation statements)

References 44 publications

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“…To the best of our knowledge, NA V263I has not been studied in an H3N2 background yet. However, a comprehensive study of NA V263I involvement at the structural level suggested the isoleucine, which is two methyl groups higher than a valine, could allow important changes by altering hindrance effects [37]. It was also suggested that this site was part of an epitope that was suitable for therapeutic monoclonal antibodies, and that an amino acid change at this position modified the immune response [38].…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

Simon

Pichon

Valette

et al. 2019

Viruses

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Influenza viruses cause a remarkable disease burden and significant morbidity and mortality worldwide, and these impacts vary between seasons. To understand the mechanisms associated with these differences, a comprehensive approach is needed to characterize the impact of influenza genomic traits on the burden of disease. During 2016–2017, a year with severe A(H3N2), we sequenced 176 A(H3N2) influenza genomes using next generation sequencing (NGS) for routine surveillance of circulating influenza viruses collected via the French national influenza community-based surveillance network or from patients hospitalized in the intensive care units of the University Hospitals of Lyon, France. Taking into account confounding factors, sequencing and clinical data were used to identify genomic variants and quasispecies associated with influenza severity or vaccine failure. Several amino acid substitutions significantly associated with clinical traits were found, including NA V263I and NS1 K196E which were associated with severity and co-occurred only in viruses from the 3c.2a1 clade. Additionally, we observed that intra-host diversity as a whole and on a specific set of gene segments increased with severity. These results support the use of whole genome sequencing as a tool for the identification of genetic traits associated with severe influenza in the context of influenza surveillance.

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Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

Simon

Pichon

Valette

et al. 2019

Viruses

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“…Mutations located at the binding site can affect the structural and/or functional behaviour of the protein. However, mutations located outside the binding site could possibly alter the structure of the binding pocket and, thus, could be associated with drug resistance (Ramírez-Salinas et al, 2015). Kar & Knecht (2012) suggested that the binding pockets of the mutated N8 NAs were less flexible as compared with the binding pocket of the WT protein.…”

Section: Discussionmentioning

confidence: 99%

The significance of naturally occurring neuraminidase quasispecies of H5N1 avian influenza virus on resistance to oseltamivir: a point of concern

Schaduangrat

Phanich

Rungrotmongkol

et al. 2016

Journal of General Virology

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Viral adaptability and survival arise due to the presence of quasispecies populations that are able to escape the immune response or produce drug-resistant variants. However, the presence of H5N1 virus with natural mutations acquired without any drug selection pressure poses a great threat. Cloacal samples collected from the 2004-2005 epidemics in Thailand from Asian open-billed storks revealed one major and several minor quasispecies populations with mutations on the oseltamivir (OTV)-binding site of the neuraminidase gene (NA) without prior exposure to a drug. Therefore, this study investigated the binding between the NA-containing novel mutations and OTV drug using molecular dynamic simulations and plaque inhibition assay. The results revealed that the mutant populations, S236F mutant, S236F/C278Y mutant, A250V/V266A/P271H/G285S mutant and C278Y mutant, had a lower binding affinity with OTV as compared with the WT virus due to rearrangement of amino acid residues and increased flexibility in the 150-loop. This result was further emphasized through the IC 50 values obtained for the major population and WT virus, 104.74 nM and 18.30 nM, respectively. Taken together, these data suggest that H5N1 viruses isolated from wild birds have already acquired OTV-resistant point mutations without any exposure to a drug.

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In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

Jazmin,

Elaheh,

Manuel Jonathan

et al. 2023

Chemistry & Biodiversity

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Antiviral resistance has turned into a world concern nowadays. Influenza A H1N1 emerged as a problem at the world level due to the neuraminidase (NA) mutations. The NA mutants conferred resistance to oseltamivir and zanamivir. Several efforts were conducted to develop better anti-influenza A H1N1 drugs. Our research group combined in silico methods to create a compound derived from oseltamivir to be tested in vitro against influenza A H1N1. Here we show the results of a new compound derived from oseltamivir but with specific chemical modifications, with significant affinity either on NA (in silico and in vitro assays) or HA (in silico) from influenza A H1N1 strain. We include docking and molecular dynamics (MD) simulations of the oseltamivir derivative at the binding site onto NA and HA of influenza A H1N1. Additionally, the biological experimental results show that oseltamivir derivative decreases the lyticplaque formation on viral susceptibility assays, and it does not show cytotoxicity. Finally, oseltamivir derivative assayed on viral NA showed a concentration-dependent inhibition behavior at nM, depicting a high affinity of the compound for the enzyme, corroborated with the MD simulations results, placing our designed oseltamivir derivative as a potential antiviral against influenza A H1N1.

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Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase

Cited by 5 publications

References 44 publications

Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

The significance of naturally occurring neuraminidase quasispecies of H5N1 avian influenza virus on resistance to oseltamivir: a point of concern

In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

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