Molecular Design of Hyaluronan with Polypeptide Branches of Controlled Structure

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DESCRIPTION (provided by applicant): Hyaluronic acid (HA) is a charged polysaccharide that is virtually "invisible" to the body's immune system because of its natural abundance in connective tissues. Recently it has become possible to synthesize long polypeptides having controlled structure and containing terminal primary amines needed for grafting reactions. It is proposed to use this new technique to conjugate long polypeptide chains to the backbones of HA molecules of high molecular weight. The novel comb-branched HA derivatives so obtained are expected to be useful as chondroprotective synovia! fluid supplements, and for use in viscosurgery and in drug delivery. The polypeptides will have a narrow chain length distribution, and will contain hydrophobic amino acids (e.g. leucine) that serf-assemble into alpha-helical domains under aqueous conditions. Due to these hydrophobic branches, the HA derivative will function as an "associative thickener" that can be used in injected formulations to boost the viscoelasticity of synovial fluid for remediation of osteoarthritis (OA) at relatively low HA content. With attached branches, shorter HA chains can be used to obtain equivalent boost in viscoelasticity, and shorter HA chains are thought to be more effective in promoting intracellular signaling pathways beneficial to OA treatment. At somewhat higher concentrations, the comb-branched HA derivative could also be used as an in situ gelling biomaterial that could be injected into the body at low viscosity, and which would self-assemble into an associative network once in place inside the body. It should be possible to tune the physical properties of these materials (gel strength, viscoelasticity, viscosity shear-thinning, osmotic pressure) by judicious choice of branch length, branch spacing, and peptide chemical identity guided by molecular simulations. In future enhancements, the long branches could be used to carry antioxidants or peptide ligands beneficial for treatment of osteoarthritis. The research proposed here may lead to the development of more potent and long-lasting injectable formulations for alleviating the pain associated with arthritis, or allow certain types of surgery to be performed with less scarring.