Glycosaminoglycans and cell-surface proteoglycans (GAGs and CSPGs)

Glycosaminoglycans (GAGs) and cell-surface proteoglycans (CSPGs) are complex, highly anionic polysaccharides and glycoconjugates that constitute a major portion of the extracellular matrix and the cell-surface glycocalyx [Lindahl et al., 2017]. GAGs, including heparan sulfate, chondroitin sulfate, and hyaluronan, consist of repeating disaccharide units and are often covalently attached to core proteins to form proteoglycans such as syndecans and glypicans [Iozzo & Schaefer, 2015]. These molecules serve as critical regulators of the cellular microenvironment by sequestering and presenting growth factors, chemokines, and morphogens to their signaling receptors, thereby controlling processes like cell proliferation, migration, and tissue morphogenesis [Nikolova & Fayad, 2014]. In pathological contexts, GAGs and CSPGs are frequently exploited by pathogens, such as SARS-CoV-2 and Herpes Simplex Virus, as attachment factors for viral entry, and they play pivotal roles in tumor progression by facilitating angiogenesis and epithelial-mesenchymal transition [Clausen et al., 2020; Afratis et al., 2012]. Therapeutic strategies targeting this class include the use of heparin-based anticoagulants and GAG mimetics designed to disrupt protein-glycan interactions in cancer and inflammatory diseases [Morla, 2019].

Other names

MucopolysaccharidesHeparan sulfate proteoglycansHSPGsChondroitin sulfate proteoglycansCSPGsExtracellular matrix polysaccharidesCellular glycocalyx components

Drugs targeting these molecules typically act as mimetics that competitively inhibit the binding of endogenous ligands (such as growth factors or viral proteins) to cell-surface GAGs, or they potentiate the activity of natural inhibitors like antithrombin III through allosteric modulation [Varki et al., 2017; Karamanos et al., 2018].