Modulation of Heparanase-Inhibiting Activity of Heparin Through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Naggi, Annamaria; Pérez, Mar; Torri, G.; Giannini, Giuseppe; Penco, Sergio; Pisano, Claudio; Vlodavsky, Israël; Casu, Benito

doi:10.1100/tsw.2002.486

Cited by 46 publications

(110 citation statements)

References 0 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…As illustrated in Fig. 8, glycol-splitting enhances the activity of N-acetylated heparins irrespective of their N-acetylation level, the most notable activity increase being observed at about 70 % N-acetylation [40]. As earlier observed for lipoprotein lipase [41] and system- Fig.…”

Section: Targeting Heparanasesupporting

confidence: 77%

“…This observation prompted revisitation of heparins and heparin derivatives as heparanase inhibitors. Whereas removal of 2-O-sulfate groups was confirmed to have little effect on the inhibition activity as previously reported [37], the activity increased with increasing content of 6-O-sulfate groups [40]. Using a more sensitive test than in previous reports, fully N-acetylated heparin was found to be one order of magnitude less active as heparanase inhibitor than heparin.…”

Section: Targeting Heparanasesupporting

confidence: 70%

“…As earlier observed for lipoprotein lipase [41] and system- Fig. 8 Heparanase inhibition by heparin at different degrees of N-acetylation ( ) and of the same products after glycol-splitting of nonsulfated uronic acid residues (○) [40].…”

Section: Targeting Heparanasementioning

confidence: 63%

“…However, whereas the strongest inhibition of FGF2 was observed by generating additional glycol-split residues along the heparin chain [30,31], the few glycol-split uronic acid residues of RO-H seem to exert very much the same influence as in the presence of additional glycol-split residues [40].…”

Section: Targeting Heparanasementioning

confidence: 95%

See 3 more Smart Citations

Antiangiogenic heparin-derived heparan sulfate mimics

Casu

Naggi

2003

Pure and Applied Chemistry

Self Cite

View full text Add to dashboard Cite

Heparan sulfate (HS) is a glycosaminoglycan (GAG) widely distributed as a proteoglycan on the cell surface and in the extracellular matrix of animal tissues. Among other important physiological functions, its polysaccharide chains mediate cell proliferation by binding growth factors [fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF)], which are released in active form through the action of the enzyme heparanase overexpressed by tumor cells. HS is constituted of alternating disaccharide sequences of variously sulfated uronic acid (D-glucuronic, GlcA, or L-iduronic, IdoA) and glucosamine (Nacetylated, GlcNAc, or N-sulfated, GlcNSO 3 ). HS mimics can be obtained by chemical modification of heparin, a more highly sulfated GAG clinically used as an anticoagulant and antithrombotic drug. With the aim of obtaining antagonists of FGFs as potential inhibitors of tumor neo-vascularization (angiogenesis), arrays of short FGF-binding sequences have been obtained by generating sulfation gaps within the prevalent (IdoA2SO 3 -GlcNSO 3 6SO 3 ) n sequences of heparin, by controlled base-catalyzed removal of 2-O-sulfate groups of IdoA2SO 3 residues. The C(2)-C(3) bond of all nonsulfated uronic acid residues have then been split with periodate, to generate flexible joints along the polysaccharide chain. The novel heparin derivative (poly-PST.sU), chiefly made up of the repeating tetrasaccharide units -GlcNSO 3 6SO 3 -IdoA2SO 3 -GlcNSO 3 6SO 3 -sU-(where sU is a glycol-split and reduced uronic acid residue) binds FGF2 as strongly as heparin. However, it is a poor inducer of formation of FGF2 dimers and of complexes with FGF receptors, required for triggering mitogenic signals. NMR and molecular modeling studies indicate that formation of these higherorder complexes is prevented by the unfavorable conformation induced by glycol-split residues. In a parallel study, partially N-acetylated heparins have been obtained that efficiently inhibit heparanase upon glycol-splitting. It is noteworthy that glycol-splitting involves inactivation of the active site for antithrombin, with consequent loss of anticoagulant activity. In contrast, poly-PST.sU and some of its analogs show potent antiangiogenic activity in in vivo models in which heparin is either proangiogenic or inactive.

show abstract

Section: Targeting Heparanasesupporting

confidence: 77%

Section: Targeting Heparanasesupporting

confidence: 70%

Section: Targeting Heparanasementioning

confidence: 63%

Section: Targeting Heparanasementioning

confidence: 95%

See 2 more Smart Citations

Antiangiogenic heparin-derived heparan sulfate mimics

Casu

Naggi

2003

Pure and Applied Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Modified heparin fragments, especially N-acetylated glycol-split heparins, are efficient and specific and used as heparanase inhibitors (Bitan et al 1995;Ferro et al 2004). Unfortunately, these substances are very rapidly inactivated, more rapidly than unfractioned heparin (Naggi et al 2005). The latest observations with sulodexide (an oral low-molecularweight heparin-like compound) indicate that the hindrance of its short action duration can be successfully overcome (Lewis and Xu 2008).…”

Section: Heparanase Inhibitorsmentioning

confidence: 99%

The Role of Heparanase in Diseases of the Glomeruli

Szymczak

Kuźniar

Klinger

2010

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.

show abstract

Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: Growth regulation and the prospect of new cancer therapies

Sanderson¹,

Yang²,

Kelly³

et al. 2005

J of Cellular Biochemistry

140

109

View full text Add to dashboard Cite

Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expressionrelated changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii)

show abstract

Modulation of Heparanase-Inhibiting Activity of Heparin Through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Cited by 46 publications

References 0 publications

Antiangiogenic heparin-derived heparan sulfate mimics

Antiangiogenic heparin-derived heparan sulfate mimics

The Role of Heparanase in Diseases of the Glomeruli

Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: Growth regulation and the prospect of new cancer therapies

Contact Info

Product

Resources

About