Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Although carbohydrate-based heparanase have been developed, but none were translated into use in the clinic. Due to its being a desirable and druggable target for anti-cancer therapy, many molecules have been developed, but only four carbohydrates have advanced to clinical trials. Owing to their heparin-based nature, these molecules are heterogeneous in size and sulfation pattern leading to nonspecific binding and unforeseen adverse effects, therefore halting their translation into clinical use. Our goal in this grant is to develop cost-effective strategies, aided by computational technique, for rapidly generating glycopolymers and oligosacharides with well- defined sulfation pattern and at the same time via a synthetic route that is capable of supporting subsequent scale up. Aminoglycosides are attractive in this light as they are commercially available and inexpensive. Aminoglycosides target 16S bacterial ribosomal RNA and inhibit protein synthesis. They are poly-cationic pseudo-oligosaccharides at physiological pH. Our approach is to transform positively charged aminoglycosides into a novel class of negatively charged aminoglycans, which no longer bind to rRNA, but can interact with heparanase.
In Aim 1, we propose strategies for expedited and scalable synthesis of sulfated glycopolymers, derived from paromomycin and neomycin, which possess similar structures and multivalent properties found in the naturally existing HS polysaccharides.
In Aim 2, we have identified commercially available and low-cost apramycin as an ideal candidate for modification to produce the sulfated pseudo-oligosaccharides as potential heparanase inhibitors.
In Aim 3, we propose strategies for expedited synthesis of sulfated pseudo-oligosaccharides by recombining 3-aminosugar unit of kanamycin with its corresponding pseudo-disaccharide unit. These pseudo- oligosaccharides possess similar structure and properties of the naturally existiing HS oligosaccharides.
Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Our goal is to develop cost-effective strategies for quickly transforming commercially available, positively charged aminoglycosides into novel classes of negatively charged aminoglycans, which no longer bind to bacterial ribosomal RNA and inhibit protein synthesis, but specifically bind to heparanase. If successfully, this strategy will allow access a wide variety of heparanase inhibitors for functional studies, early clinical development and cancer therapeutic applications.
