Cell-surface heparan sulfate proteoglycan (HSPG)

Cell-surface heparan sulfate proteoglycans (HSPGs) are a diverse group of glycoproteins characterized by a core protein covalently linked to heparan sulfate (HS) glycosaminoglycan chains [4, 7]. Primarily represented by the syndecan and glypican families, these molecules are ubiquitously expressed on the plasma membrane where they function as essential co-receptors for various growth factors, chemokines, and morphogens [10, 13]. By modulating signaling pathways such as FGF, VEGF, and Wnt, HSPGs play critical roles in cell proliferation, adhesion, and migration [6, 14]. In pathological contexts, HSPGs are frequently dysregulated; they facilitate tumor angiogenesis and metastasis in cancer, act as attachment receptors for viruses like SARS-CoV-2 and HIV, and promote the aggregation of amyloid proteins in neurodegenerative diseases [5, 9, 11]. Therapeutic strategies targeting HSPGs include heparan sulfate mimetics that competitively inhibit ligand binding, monoclonal antibodies against specific core proteins like Glypican-3 or Syndecan-1, and inhibitors of heparan-remodeling enzymes like heparanase [2, 4, 9]. However, the ubiquitous nature of HSPGs presents challenges for drug specificity and potential off-target effects, such as interference with coagulation or wound healing [9, 10].

Other names

SyndecansGlypicansMembrane-associated heparan sulfate proteoglycansCell-surface HSPGsHeparan sulfate proteoglycans

Drugs targeting cell-surface heparan sulfate proteoglycans (HSPGs) primarily utilize heparan sulfate mimetics to competitively inhibit the binding of growth factors, chemokines, and viral proteins to the HS chains [4, 9]. Other approaches include the use of monoclonal antibodies or antibody-drug conjugates to target specific core proteins like Syndecan-1 or Glypican-3 for cell depletion or signaling blockade [2, 8]. Additionally, small molecule inhibitors target enzymes such as heparanase and sulfatase-2, which remodel HSPGs to release sequestered ligands and promote tumor progression [7, 9].