Rational design of peptide ligands against a glycolipid by NMR studies.

Ganglioside GD2 is a cell surface glycosphingolipid that is targeted clinically for cancer diagnosis, prognosis, and therapy. The conformations of free GD2 and of GD2 bound to anti-GD2 mAb 3F8 were resolved by saturation transfer difference nuclear magnetic resonance and molecular modeling. Then small molecule cyclic peptide ligands that bind to GD2 selectively were designed, and shown to affect GD2-mediated signal transduction. The solution structure of the GD2-bound conformation of the peptide ligands showed an induced-fit binding mechanism. This work furthers the concept of rationally designing ligands for carbohydrate targets; and may be expanded to other clinically relevant gangliosides.