Design and synthesis of artificial glycopolypeptides as mediators of biologically relevant binding events.

摘要

Toxins and pathogens achieve highly efficient and selective binding through multivalent interactions between relevant oligosaccharides and saccharide receptors on each toxin/pathogen subunit. Because of the important role played by protein-carbohydrate interactions in these pathogenic events and in other human diseases, considerable effort has been devoted toward the development of high-affinity ligands for carbohydrate binding proteins. Multivalent ligands synthesized via traditional polymer techniques have provided valuable insight as to the general guidelines that govern these multivalent interactions, but are inherently limited by an inability to effectively control the molecular weight, polydispersity, sequence, and/or geometrical placement of the saccharide moiety on the glycopolymer. This lack of control makes it virtually impossible to determine the origins of increased binding activity. The synthesis of polymers via protein engineering methods allows control over the molecular weight, as well as the number and spacing of saccharides on a scaffold, which permits the structure-based design of polypeptide-based polymers for inhibition of such multivalent binding events. As such, we have employed a combination of protein engineering techniques and chemical methods to produce a family of galactose-functionalized glycopolymers with different backbone compositions and architectures in which the density, saccharide spacing, and linker length of the pendent carbohydrate moieties have been varied. Such ligands may disrupt pathological carbohydrate-mediated recognition and act as a fundamentally new class of noncytotoxic therapeutic agents with broad applicability to a wide range of human disease; in addition, investigations like these will aid in the deconvolution of the impact of multivalency, spacing, and backbone rigidity in a variety of biologically relevant binding events.