Počet záznamů: 1  

Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza

  1. 1.
    0463882 - UOCHB-X 2017 RIV FR eng J - Článek v odborném periodiku
    Albinana, C. B. - Machara, A. - Řezáčová, Pavlína - Pachl, Petr - Konvalinka, Jan - Kožíšek, Milan
    Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza.
    European Journal of Medicinal Chemistry. Roč. 121, Oct 4 (2016), s. 100-109. ISSN 0223-5234
    Grant CEP: GA ČR GA13-19561S; GA MŠk LO1302; GA MŠk(CZ) LO1304
    Institucionální podpora: RVO:61388963
    Klíčová slova: influenza neuraminidase * oseltamivir * tamiphosphor * isothermal titration calorimetry * crystal structure * lattice-translocation defect
    Kód oboru RIV: CE - Biochemie
    Impakt faktor: 4.519, rok: 2016

    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 angstrom resolution. This structural information should aid rational design of the next generation of neuraminidase inhibitors.
    Trvalý link: http://hdl.handle.net/11104/0262963