Polyproline Tri-Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions.

Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sites arrangement. The GalNAc pattern selectivity is also observed on intact asialoglycoprotein receptor oligomer on human hepatoma cells showing the pattern-selective interaction can be achieved not only on isolated protein oligomers but also the receptors arranged on the cell surface. As the scaffold design allows convenient creation of versatile ligand patterns, it can be expected as a promising tool to probe the arrangement of receptors on the cell surface and as nanomedicine to manipulate signaling or cell recognition.

Selective targeting of DC-SIGN by controlling the oligomannose pattern on a polyproline tetra-helix macrocycle scaffold.

DC-SIGN and langerin receptors both bind to oligomannose but lead to opposite effects upon encountering HIV. Because selective targeting of DC-SIGN can lead to anti-viral effects, we developed a glycoconjugate, which provides over 4800-fold selectivity for DC-SIGN over langerin, by controlling the oligomannose pattern on a polyproline tetra-helix macrocycle scaffold.