The project workplan is based on the concept that heparanase inhibitors, more effective than the few ones described to date, can be designed and generated through identification of the structural requirements for HS and HS-like oligo- and polysaccharides to be recognized as substrates by the enzyme. The availability of recombinant heparanase makes it possible to map the binding site(s) of the enzyme for HS, as well as to identify the specific structure and molecular conformation of the HS sequences required for recognition by the enzyme. This information could be effectively used to design and synthesize oligosaccharides recognized, but not cleaved, by the enzyme. In a parallel approach, it will also permit the generation, by semi-synthesis, of sulfated oligo- and polysaccharides optimal for enzyme inhibition. The novel, optimized heparanase inhibitors will be further screened for their in vitro antiangiogenic activity and for their antiangiogenic and antimetastatic activity in experimental animal models.