Enzymatic Copolymerization to Hybrid Glycosaminoglycans:  A Novel Strategy for Intramolecular Hybridization of Polysaccharides

Hybrid glycosaminoglycans (GAGs) having an intramolecularly hybridized structure of hyaluronan−chondroitin (3a) and hyaluronan−chondroitin 4-sulfate (3b) have been synthesized via enzymatic copolymerization catalyzed by hyaluronidase (HAase). N-Acetylhyalobiuronate (GlcAβ(1→3)GlcNAc)-derived oxazoline (1) was copolymerized with N-acetylchondrosine (GlcAβ(1→3)GalNAc)-derived oxazoline (2a) by HAase catalysis at pH 7.5 and 30 °C, giving rise to copolymer 3a with M n 7.4 × 103 in a 50% yield. Also, HAase-catalyzed copolymerization of monomer 1 with N-acetylchondrosine oxazoline having a sulfate group at C4 on GalNAc (2b) was carried out to produce copolymer 3b with M n 1.4 × 104 in a 60% yield. The copolymer compositions were controllable by varying the comonomer feed ratio. These hybrid GAGs were successfully digested by the catalysis of hyaluronan lyase, clearly exhibiting that the products are not a blend of different homopolymers but an intramolecularly hybridized GAG.