Effects of polymer structure on the inhibition of cholera toxin by linear polypeptide-based glycopolymers.
A variety of important biological events are mediated by the multivalent interaction between relevant oligosaccharides and multiple saccharide receptors on lectins, toxins, and cell surfaces; a variety of glycopolymeric materials have therefore been investigated in studies aimed at manipulating these events. The synthesis of protein- and polypeptide-based glycopolymers via protein engineering and other methods offers opportunities to control both the number and the spacing of saccharides on a scaffold, as well as the conformation of the polymer backbone, and will therefore facilitate the structure-based design of polymers for inhibition of multivalent binding events. In initial studies, we have synthesized a family of galactose-functionalized glycopolymers with a poly(L-glutamic acid) backbone, in which the density and linker length of the pendant carbohydrate moiety were varied. The composition of the glycopolymers was determined via (1)H NMR spectroscopy, and the impact of saccharide density and linker length, as well as the potential for these polypeptide-based glycopolymers to act as high-affinity inhibitors of the cholera toxin, has been indicated via competitive enzyme-linked immunosorbent assay and fluorescence titration experiments. The results of these studies suggest strategies for optimizing the binding of linear glycopolymers to bacterial toxins and will aid in the design of additional protein-based materials for studying the impact of multivalency, spacing, and backbone rigidity in a variety of biologically relevant binding events.
Polizzotti
Brian D
BD
Department of Materials Science and Engineering and Delaware Biotechnology Institute, University of Delaware, 201 DuPont Hall, Newark, 19716, USA.
Kiick
Kristi L
KL
D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005690:Galactose / Q000737:chemistry; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011099:Polyglutamic Acid / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006020:Glycopeptides; D011108:Polymers; D011099:Polyglutamic Acid; D002772:Cholera Toxin; D005690:Galactose