title: Targeting norovirus infection-multivalent entry inhibitor design based on NMR experiments.
abstract: 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.
authors.affiliation: Center of Structural and Cell Biology in Medicine, Institute of Chemistry, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.forename: Julie
authors.initials: J
authors.lastname: Guiard
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Kitov
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fiege
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Dalton
authors.forename: Francisco
authors.initials: F
authors.lastname: Parra
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
authors.forename: Thomas
authors.initials: T
authors.lastname: Peters
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D029322:Norovirus / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D054852:Small Molecule Libraries