Heparan sulfate and other cell-surface glycosaminoglycans (HS/GAGs)

Heparan sulfate (HS) and other cell-surface glycosaminoglycans (GAGs) are complex, highly acidic linear polysaccharides that are typically covalently attached to core proteins to form proteoglycans. These molecules are ubiquitously expressed on the surfaces of almost all animal cells and within the extracellular matrix, where they serve as critical scaffolds for protein-protein interactions. By binding to a diverse array of ligands, including growth factors, chemokines, and morphogens, HS/GAGs regulate essential physiological processes such as cell proliferation, differentiation, and blood coagulation. In various pathologies, these polysaccharides are exploited by viruses and bacteria for cell attachment and are involved in the modulation of the tumor microenvironment to promote angiogenesis and metastasis. Therapeutically, GAGs are most notably targeted or mimicked by anticoagulant drugs like heparin, which enhance the activity of antithrombin. Emerging therapeutic strategies focus on using GAG mimetics to disrupt pathological signaling in cancer and inflammatory diseases or to block the entry of infectious pathogens into host cells.

Other names

Heparan sulfate proteoglycansHSPGsGlycosaminoglycansGAGsCell-surface polysaccharidesHeparin-like substances

Drugs targeting these molecules primarily act through competitive inhibition or structural mimicry. Anticoagulants like heparin and its derivatives bind to antithrombin III, inducing a conformational change that accelerates the inactivation of thrombin and Factor Xa (Source: StatPearls, 2023). Other agents, such as GAG mimetics, compete with endogenous heparan sulfate for binding to viral proteins or growth factors, thereby blocking viral entry or inhibiting pro-angiogenic signaling in tumors (Source: British Journal of Pharmacology, 2020). Additionally, some drugs inhibit heparanase, the enzyme responsible for degrading HS, to maintain basement membrane integrity (Source: Cancer Microenvironment, 2013).