Heparanase is the only mammalian endo-β-glucuronidase known to catalyse the degradation of heparan sulfate chains and its activity has been linked with a variety of diseases, such as diabetes and cancer. Heparan sulfate mimetics are highly sulfated, synthetic or semisynthetic compounds that have demonstrated some value as potential anti-cancer agents due to their ability to inhibit heparanase1, however, the interactions of these oligosaccharides with the protein have not been characterised quantitatively. It is essential we understand how these molecules inhibit heparanase, what species within their heterogeneous mixtures are the most active, and whether we can utilise these molecules as drugs.
Analysis of new oligosaccharide mimetics fucoidan and pentosan polysulfate was conducted. This involved separation of the compounds and the synthesis of molecular species with defined length. Both molecules were found to be potent and competitive inhibitors, with the length of pentosan contributing to the affinity of these molecules to heparanase. Having identified precise molecular species with high potency, we addressed some of the pharmacokinetic issues related to limitations of oligosaccharides as drugs by characterizing their interaction with a hydrogel-based drug delivery system. This work has advanced our understanding of how heparan sulfate mimetics interact with heparanase, heralding new advances towards the treatment of cancer, macular degeneration, and related diseases.