Heparin-derived heparan sulfate mimics to modulate heparan sulfate-protein interaction in inflammation and cancer

Abstract

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 heparinderived 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.

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

“…This alters the essential GlcA residue within the ATBR and drastically reduces the 45 A similar effect is obtained by N-acetylation, which modifies the essential fully sulfated glucosamine of the ATBR sequence. The nonanticoagulant heparins produced in these ways retain biological activities unrelated to coagulation, such as antiheparanase, 55 anti-inflammatory 43 and antiangiogenesis activity. 42,56 Some of them have been proposed for clinical treatment of solid tumors.…”

“…40 Thus, heparin capacity to interfere with BMPs signaling may be unrelated with anticoagulant activity, and heparins with little/no anticoagulant activity retain various biological activities such as antiheparanase, 41 antiangiogenesis, 42 and antiinflammation. 43 Heparins with high antihepcidin activity and low anticoagulant activity may be useful for the treatment of disorders with hepcidin excess. Here we studied the functionality of chemically modified heparins with different degrees of sulfation, N-acetylation, and chain flexibility that lost antithrombin binding affinity and have a strongly reduced anticoagulant activity.…”

Heparan sulfate disaccharide measurement from biological samples using pre-column derivatization, UPLC-MS and single ion monitoring

“…Although the molecular mechanism of the action of GAGs is not well understood, accumulating evidence suggests that the effects of heparan sulfate glycosaminoglycans may be attributable at least in part to their binding of the growth factors and regulating of their signaling [6,7].…”

Low-Anticoagulant Heparins in the Treatment of Metastasis

“…However, shortly after its initial discovery, it was reported that heparin had an inhibitory effect on tumor growth in animals (Goerner, 1930). This initial observation led to intensive investigation with regard to heparin's anticancer and anti-metastatic properties (Casu et al, 2010;Casu et al, 2008;Hettiarachchi et al, 1999;Kragh & Loechel, 2005;Lapierre et al, 1996;Lever & Page, 2002;Ono et al, 2002;Ornstein & Zacharski, 1999;Smorenburg et al, 1996;Stevenson et al, 2005;Stevenson et al, 2007;Vlodavsky et al, 2006;Yip et al, 2006;Yoshitomi et al, 2004). The usefulness of heparin as an anticancer drug has been hindered by its anticoagulant effect at therapeutic doses required to inhibit cancer growth and spread.…”