Stapling of β-Glucans Increases Antibody Binding

Higher-order structures are essential for the function of biological macromolecules. Tuning the conformational space of peptides by stapling improves their pharmacological properties. The three-dimensional (3D) structures of glycans are much less well understood than those of peptides and oligonucleotides, and willful modulation of oligosaccharide structures to improve binding to proteins has not been described to date. Herein, we describe stapling of β-(1,3)-glucans to tune their conformation, aiming to mimick the naturally occurring triple helix. The stapled glycans are prepared by automated glycan assembly, followed by linker construction and ring-closure assisted by solid-phase peptide synthesis. Thereby, staples of different lengths, polarities, and topologies can be readily introduced. Molecular dynamics simulations served to evaluate the effect of stapling on the conformational space. Glycan microarray experiments revealed that stapled glycans bound significantly more tightly to monoclonal mouse and rabbit antibodies than did linear glycans. Controlling the conformational space of short oligosaccharides creates opportunities for synthetic glycans in drug and vaccine development.