Heparan sulfate proteoglycan (HSPG) (HSPG)

Heparan sulfate proteoglycans (HSPGs) are a diverse class of glycoproteins characterized by a core protein covalently linked to heparan sulfate (HS) glycosaminoglycan chains [9, 10]. Located on the cell surface and within the extracellular matrix, they function primarily as co-receptors that facilitate the binding and signaling of various ligands, including growth factors (e.g., FGF, VEGF), cytokines, and morphogens [11, 12]. HSPGs play critical roles in regulating cell proliferation, adhesion, and migration, and they are frequently dysregulated in pathological conditions such as cancer, where they promote tumor progression and angiogenesis [2, 9]. Additionally, they serve as essential attachment factors for numerous pathogens, including SARS-CoV-2 and HIV, facilitating viral entry into host cells [7, 8]. Therapeutic strategies targeting HSPGs include the use of HS mimetics to competitively inhibit ligand binding, inhibitors of HS-modifying enzymes like heparanase, and monoclonal antibodies directed against specific core proteins like Glypican-3 [5, 13]. In the context of cancer, HSPGs like Glypican-3 and Syndecan-1 are often overexpressed and serve as biomarkers for diagnosis and targets for antibody-drug conjugates [4, 14]. Beyond oncology, these receptors are involved in inflammatory processes by modulating chemokine gradients and leukocyte recruitment [10, 14]. Drugs targeting this class often aim to disrupt the sugar code—the specific sulfation patterns that dictate protein-binding specificity—to achieve therapeutic effects while minimizing interference with normal physiological functions [14, 15].

Other names

Heparan sulfate/heparin-like cell-surface receptorsCell-surface heparan sulfate proteoglycansHeparin-like receptorsSyndecansGlypicansMembrane-associated heparan sulfate proteoglycans

Drugs targeting heparan sulfate proteoglycans primarily act through competitive inhibition of ligand binding using heparan sulfate mimetics, inhibition of modifying enzymes such as heparanase and sulfatase, or direct antagonism of glycosaminoglycan-protein interactions to disrupt signaling and viral entry [2, 5, 15].