The involvement of the Heparanase enzyme (HPSE) in the proliferation of cancer has garnered intense interest as an anticancer strategy. HPSE is a principal enzyme involved in multiple biological pathways and is expressed in mammalian cells as a single dominant functional enzyme. Normal expression of HPSE plays a vital role in maintaining the extracellular matrix (ECM) such as immune cell migration, wound healing, and angiogenesis. However, clinical studies illustrate that increased expression of HPSE is linked to increased tumor growth and enhanced metastasis, which leads to a poor prognosis for patients with solid tumors. As such, there is a need for Heparanase inhibitors but only a select few carbohydrate Heparan Sulfate mimetics have made it to clinical trials. HPSE selectively cleaves the internal β-(1, 4)-linkage between glucuronic acid (GlcA) and the glucosamine (GlcN) unit on heparan sulfate (HS) chains which exist on the cell surface as proteoglycans. With the aid of computational studies, we identified the aminoglycoside antibiotic Paromomycin as an ideal candidate for chemical modification toward the binding and inhibition of HPSE. Paromomycin is a pseudo-tetra saccharide with a 2-deoxystreptamine ring at its core. Our work showed that selectively sulfating the free amines on Paromomycin allows it to bind to the positively charged pockets of the Heparanase enzyme. We also elucidated that a 6-O-SO3- and a 5’-O-SO3- increased binding affinity to HPSE.

Design and development of sulfated Paromomycin analogs as a heparanase enzyme inhibitor

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