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.

Inhibition of CD45 Phosphatase Activity Induces Cell Cycle Arrest and Apoptosis of CD45+ Lymphoid Tumors Ex Vivo and In Vivo

“…The lymph node volume was calculated from the diameter using the equation V 5 (4pr 3 )/3, and the measurements were standardized to normal lymph node volume. The tissues were studied by immunohistochemistry using anti-GD2 mAbs (a ganglioside marker of EL4 tumor cells), as described by Tong et al (2010).…”

Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a

“…Another interesting approach to obtain peptide sequences is the de novo design of mimetics. Tong et al reported recently that peptidic Gd2 ligands were rationally designed based on NMR and molecular modeling analyses of Gd2 in free form and bound to the anti-Gd2 mAb 3F8 (38).…”

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

“…As also proposed, engineering the mimotope into a hybrid plasmid, which can also include cytotoxic T-lymphocyte epitopes from a tumor target itself, would be expected to build an effector response that could improve the tumor-protective immunity evoked by the minigene vaccine (121). Finally, studies are also being focused on the development of new strategies for therapeutic intervention in cancer, which propose the use gangliosides for targeted delivery of cytotoxic agents via specific antibodies (32), or eventually, via small-molecule cyclic peptide ligands (123). …”