title: Small-molecule ligands of GD2 ganglioside, designed from NMR studies, exhibit induced-fit binding and bioactivity.
abstract: Ganglioside GD2 is a cell surface glycosphingolipid. Targeting of GD2, i.e., by anti-GD2 mAb 3F8, is used clinically for cancer diagnosis, prognosis, and therapy. Here, the conformations of free GD2, and of GD2 bound to mAb 3F8, were resolved by saturation transfer difference NMR and molecular modeling. Then, three small-molecule cyclic peptide ligands that bind to GD2 selectively were designed. Transferred nuclear Overhauser enhancement of the GD2-bound conformation of the peptide ligands showed an induced-fit binding mechanism. The mAb 3F8 and the peptidic GD2 ligands mediate similar biological functions in cell-based assays of calcium fluxes and src activation. Thus, small molecules can selectively and functionally interact with a sugar head group. This work furthers the concept of rationally designing ligands for carbohydrate targets, and may be expanded to other clinically relevant gangliosides.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montréal, QC, Canada, H3T 1E2.
authors.forename: Wenyong
authors.initials: W
authors.lastname: Tong
authors.forename: Martin
authors.initials: M
authors.lastname: Gagnon
authors.forename: Tara
authors.initials: T
authors.lastname: Sprules
authors.forename: Michel
authors.initials: M
authors.lastname: Gilbert
authors.forename: Shafinaz
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Karen
authors.initials: K
authors.lastname: Meerovitch
authors.forename: Karl
authors.initials: K
authors.lastname: Hansford
authors.forename: Enrico O
authors.initials: EO
authors.lastname: Purisima
authors.forename: John W
authors.initials: JW
authors.lastname: Blankenship
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005732:Gangliosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D008024:Ligands; D010456:Peptides, Cyclic; C019403:ganglioside, GD2; D019061:src-Family Kinases; D002118:Calcium