Premium
Targeting Norovirus Infection—Multivalent Entry Inhibitor Design Based on NMR Experiments
Author(s) -
Rademacher Christoph,
Guiard Julie,
Kitov Pavel I.,
Fiege Brigitte,
Dalton Kevin P.,
Parra Francisco,
Bundle David R.,
Peters Thomas
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201003432
Subject(s) - norovirus , avidity , surface plasmon resonance , chemistry , murine norovirus , ligand (biochemistry) , binding site , viral entry , rational design , stereochemistry , virology , biochemistry , virus , antigen , biology , nanotechnology , viral replication , immunology , receptor , nanoparticle , genetics , materials science
Noroviruses attach to their host cells through histo blood group antigens (HBGAs), and compounds that interfere with this interaction are likely to be of therapeutic or diagnostic interest. It is shown that NMR binding studies can simultaneously identify and differentiate the site for binding HBGA ligands and complementary ligands from a large compound library, thereby facilitating the design of potent heterobifunctional ligands. Saturation transfer difference (STD) NMR experiments, spin‐lock filtered NMR experiments, and interligand NOE (ILOE) experiments in the presence of virus‐like particles (VLPs), identified compounds that bind to the HBGA binding site of human norovirus. Based on these data two multivalent prototype entry‐inhibitors against norovirus infection were synthesized. A surface plasmon resonance based inhibition assay showed avidity gains of 1000 and one million fold over a millimolar univalent ligand. This suggests that further rational design of multivalent inhibitors based on our strategy will identify potent entry‐inhibitors against norovirus infections.