SUPRHAPOLYMERS · Engineering macromolecular self-assembly of hyaluronan (HA)-based glycopolymers with peptides

Engineering macromolecular self-assembly of hyaluronan (HA)-based glycopolymers with peptides

Hyaluronan (HA) is a unique, highly abundant extracellular matrix (ECM) polysaccharide found throughout mammalian connective tissues. It has a simple linear structure comprising solely repeating disaccharide units of N-acetyl-glucosamine and glucuronic acid. It is, however, capable of an amazing variety of conformations, ranging from extended chains to relaxed coils, which are transient and rapidly interchanging in solution. Unlike other glycosaminoglycans (GAGs), HA is neither sulphated nor attached to a core protein. This lack of chemical variation is unusual in biology and its evolutionary consistency suggests a protected status. It has been postulated that many matrix assembly processes in vertebrates have evolved around this molecule in such a way as to disfavour modified competitors. HA is also involved in the ECM organization and many other aspects of cell behaviour (migration, proliferation). Glycopolymers provide an alternative to conventional polysaccharides, by offering the possibility to display sugars across the polymer backbone at defined densities, while providing a robust polymer segment rather than the glycosidic bonds, potentially forming more stable biomaterials with similar biological activity. This project investigated the synthesis of new glycopolymers based on HA and exploited their potential biomedical applications. Several synthetic analogues (homopolymers, alternating or random glycopolymers) bearing HA sugar monomers were generated and analysed for their properties (molecular weight, charge, conformation and binding selectivity). Depending on the polymer backbone and monomer composition, HA glycopolymers with different properties were obtained. We then compared the properties of these synthetic glycopolymers with native HA of similar molecular weight. HA glycopolymers share some properties of native HA, such as water solubility and negative charge, and they have shown interaction with HA binding peptides, including peptides derived by phage display, whilst maintaining a non-cytotoxic behavior. This synthetic platform enables the generation of different variations of HA glycopolymers that can be used to elucidate the role of HA sugars in the binding to cell receptors, or to other carbohydrate-binding proteins or peptides, and also to engineer novel biomaterials based on HA. Using self-assembled monolayers (SAMs), we have also created model surfaces where a library of HA-binding peptides can be immobilized in specific locations and then test their interaction with natural HA or HA glycopoplymers. These model surfaces are now being applied to study the migration of cancer cells or to engineer the endothelial glycocalyx.

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