Heparin-derived heparan sulfate mimics to modulate heparan sulfate-protein interaction in inflammation and cancer.
The heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPG) are "ubiquitous" components of the cell surface and the extracellular matrix (EC) and play important roles in the physiopathology of developmental and homeostatic processes. Most biological properties of HS are mediated by interactions with "heparin-binding proteins" and can be modulated by exogenous heparin species (unmodified heparin, low molecular weight heparins, shorter heparin oligosaccharides and various non-anticoagulant derivatives of different sizes). Heparin species can promote or inhibit HS activities to different extents depending, among other factors, on how closely their structure mimics the biologically active HS sequences. Heparin shares structural similarities with HS, but is richer in "fully sulfated" sequences (S domains) that are usually the strongest binders to heparin/HS-binding proteins. On the other hand, HS is usually richer in less sulfated, N-acetylated sequences (NA domains). Some of the functions of HS chains, such as that of activating proteins by favoring their dimerization, often require short S sequences separated by rather long NA sequences. The biological activities of these species cannot be simulated by heparin, unless this polysaccharide is appropriately chemically/enzymatically modified or biotechnologically engineered. This mini review covers some information and concepts concerning the interactions of HS chains with heparin-binding proteins and some of the approaches for modulating HS interactions relevant to inflammation and cancer. This is approached through a few illustrative examples, including the interaction of HS and heparin-derived species with the chemokine IL-8, the growth factors FGF1 and FGF2, and the modulation of the activity of the enzyme heparanase by these species. Progresses in sequencing HS chains and reproducing them either by chemical synthesis or semi-synthesis, and in the elucidation of the 3D structure of oligosaccharide-protein complexes, are paving the way for rational approaches to the development of HS-inspired drugs in the field of inflammation and cancer, as well in other therapeutic fields.
Casu
Benito
B
G. Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy. casu@ronzoni.it
Naggi
Annamaria
A
Torri
Giangiacomo
G
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D000099175:Heparanase
D000925:Anticoagulants; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate; D016209:Interleukin-8; D009844:Oligosaccharides; D011134:Polysaccharides; D011506:Proteins; D000099175:Heparanase; C062991:AZU1 protein, human