Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
27236066
DOI
10.1016/j.ejmech.2016.05.016
PII: S0223-5234(16)30396-8
Knihovny.cz E-zdroje
- Klíčová slova
- Crystal structure, Influenza neuraminidase, Isothermal titration calorimetry, Lattice-translocation defect, Oseltamivir, Tamiphosphor,
- MeSH
- antivirové látky chemie farmakologie MeSH
- chřipka lidská virologie MeSH
- inhibitory enzymů chemie farmakologie MeSH
- katalytická doména MeSH
- kinetika MeSH
- kyseliny fosforité metabolismus terapeutické užití MeSH
- lidé MeSH
- neuraminidasa antagonisté a inhibitory metabolismus MeSH
- oseltamivir analogy a deriváty metabolismus terapeutické užití MeSH
- pandemie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- virus chřipky A, podtyp H1N1 enzymologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky MeSH
- inhibitory enzymů MeSH
- kyseliny fosforité MeSH
- neuraminidasa MeSH
- oseltamivir MeSH
- tamiphosphor MeSH Prohlížeč
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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