Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza
Language English Country France Media print-electronic
Document type Journal Article
PubMed
27236066
DOI
10.1016/j.ejmech.2016.05.016
PII: S0223-5234(16)30396-8
Knihovny.cz E-resources
- Keywords
- Crystal structure, Influenza neuraminidase, Isothermal titration calorimetry, Lattice-translocation defect, Oseltamivir, Tamiphosphor,
- MeSH
- Antiviral Agents chemistry pharmacology MeSH
- Influenza, Human virology MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Catalytic Domain MeSH
- Kinetics MeSH
- Phosphorous Acids metabolism therapeutic use MeSH
- Humans MeSH
- Neuraminidase antagonists & inhibitors metabolism MeSH
- Oseltamivir analogs & derivatives metabolism therapeutic use MeSH
- Pandemics MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Influenza A Virus, H1N1 Subtype enzymology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antiviral Agents MeSH
- Enzyme Inhibitors MeSH
- Phosphorous Acids MeSH
- Neuraminidase MeSH
- Oseltamivir MeSH
- tamiphosphor MeSH Browser
Influenza virus causes severe respiratory infections that are responsible for up to half a million deaths worldwide each year. Two inhibitors targeting viral neuraminidase have been approved to date (oseltamivir, zanamivir). However, the rapid development of antiviral drug resistance and the efficient transmission of resistant viruses among humans represent serious threats to public health. The approved influenza neuraminidase inhibitors have (oxa)cyclohexene scaffolds designed to mimic the oxonium transition state during enzymatic cleavage of sialic acid. Their active forms contain a carboxylate that interacts with three arginine residues in the enzyme active site. Recently, the phosphonate group was successfully used as an isostere of the carboxylate in oseltamivir, and the resulting compound, tamiphosphor, was identified as a highly active neuraminidase inhibitor. However, the structure of the complex of this promising inhibitor with neuraminidase has not yet been reported. Here, we analyzed the interaction of a set of oseltamivir and tamiphosphor derivatives with neuraminidase from the A/California/07/2009 (H1N1) influenza virus. We thermodynamically characterized the binding of oseltamivir carboxylate or tamiphosphor to the neuraminidase catalytic domain by protein microcalorimetry, and we determined crystal structure of the catalytic domain in complex with tamiphosphor at 1.8 Å resolution. This structural information should aid rational design of the next generation of neuraminidase inhibitors.
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