Design of Paromomycin and Neomycin as Sulfated and Hydrophobic Glycans to Target Heparanase-Driven Tumor Progression and Metastasis.

ABSTRACT: Heparanase (HPSE) is the sole mammalian endoglycosidase that degrades heparan sulfate (HS) proteoglycans, disrupting the extracellular matrix (ECM) and promoting cancer invasion and metastasis. Although HPSE overexpression is linked to tumor progression, no clinically approved HPSE inhibitors exist. We developed aminoglycoside-based HS mimetics with defined sulfation and hydrophobic modifications to target HPSE's lipophilic pockets, a novel approach distinct from traditional HS glycans. Computational modeling showed that these mimetics engage HPSE through hydrophobic and π-π stacking interactions, enhancing affinity. The most potent compounds inhibited HPSE-driven ECM degradation, tumor cell proliferation, and invasion. In vivo, the lead candidate significantly reduced metastatic bu

SUBMITTER: Abdulsalam H 

PROVIDER: S-EPMC12184805 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature