Large-scale preparation of the oligosaccharide phosphate fraction of Pichia holstii NRRL Y-2448 phosphomannan for use in the manufacture of PI-88

Ferro, Vito; Fewings, Kym; Palermo, Maria C; Li, Caiping

doi:10.1016/s0008-6215(01)00061-1

Cited by 57 publications

(39 citation statements)

References 19 publications

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“…PI-88, provided by Progen Industries Limited (Brisbane, Australia), was prepared as previously described Ferro et al, 2001) by the sulfation of phosphomanno-oligosaccharides derived from the phosphomannan produced by the yeast Pichia holsti. It consists predominantly of sulfated phosphomannopentaose and phosphomannotetraose with its components having a molecular mass range of B1400 to B3100 Da.…”

Section: Pi-88 Preparationmentioning

confidence: 99%

A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

et al. 2005

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Section: Pi-88 Preparationmentioning

confidence: 99%

A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

et al. 2005

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“…Reagents-PI-88, provided by Progen Industries Ltd. (Brisbane, Australia), was prepared as described previously (24,27) by the sulfation of phosphomanno-oligosaccharides derived from the phosphomannan produced by the yeast Pichia holsti. It consists predominantly of sulfated phosphomannopentaose and phosphomannotetraose with its components having molecular masses in the range ϳ1400 to ϳ3100 Da.…”

Section: Methodsmentioning

confidence: 99%

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Freeman¹,

Liu

Banwell

et al. 2005

Journal of Biological Chemistry

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Heparin and heparan sulfate (HS) are structurally diverse glycosaminoglycans (GAG) that are known to interact, via unique structural motifs, with a wide range of functionally distinct proteins and modulate their biological activity. To define the GAG motifs that interact with proteins, we assessed the ability of 15 totally synthetic HS mimetics to interact with 10 functionally diverse proteins that bind heparin/HS. The HS mimetics consisted of cyclitol-based pseudo-sugars coupled by linkers of variable chain length, flexibility, orientation, and hydrophobicity, with variations in sulfation also being introduced into some molecules. Three of the proteins tested, namely hepatocyte growth factor, eotaxin, and elastase, failed to interact with any of the sulfated linked cyclitols. In contrast, each of the remaining seven proteins tested exhibited a unique reactivity pattern with the panel of HS mimetics, with tetrameric cyclitols linked by different length alkyl chains being particularly informative. Thus, compounds with short alkyl spacers (2-3 carbon atoms) effectively blocked the interaction of fibroblast growth factor-1 (FGF-1) and lipoprotein lipase with heparin/HS, whereas longer chain spacers (7-10 carbon atoms) were required for optimal inhibition of FGF-2 and vascular endothelial growth factor binding. This effect was most pronounced with the chemokine, interleukin-8, where alkyl-linked tetrameric cyclitols were essentially inactive unless a spacer of >7 carbon atoms was used. The heparin-inhibitable enzymes heparanase and cathepsin G also displayed characteristic inhibition patterns, cathepsin G interacting promiscuously with most of the sulfated cyclitols but heparanase activity being inhibited most effectively by HS mimetics that structurally resemble a sulfated pentasaccharide. These data indicate that a simple panel of HS mimetics can be used to probe the HS binding specificity of proteins, with the position of anionic groups in the HS mimetics being critical. Heparan sulfate (HS)1 is a glycosaminoglycan that is ubiquitously expressed as a proteoglycan on cell surfaces and throughout the extracellular matrix (ECM) in most multicellular animals (1-5). The polysaccharide is composed of alternating glucuronic acid and N-acetylglucosamine units, which, during biosynthesis, are subjected to a range of modifications such as O-sulfation at various positions, N-deacetylation, and Nsulfation of N-acetylglucosamine residues as well as C-5 epimerization of glucuronic acid to iduronic acid. Theoretically up to 48 different disaccharides could occur in HS due to these modifications, although so far only 23 have been identified (2). Nevertheless, as a result of the presence of these different disaccharides, HS chains exhibit remarkable structural heterogeneity. Such diversity is further enhanced by the considerable variation in chain length of the glycosaminoglycan. Heparin, a glycosaminoglycan with a much more restricted cellular distribution than HS, is structurally closely related to HS but has ϳ80% of its disacc...

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“…Phosphomannopentaose sulfate (PI-88) (Progen Industries Limited) is a sulfated oligosaccharide with a molecular weight of 2100 to 2585 and was prepared as previously described 1,8 by the sulfation of phosphomannopentaose derived from the phosphomannan produced by the yeast Pichia holstii. PM5 is a minimally sulfated backbone counterpart of PI-88 with a molecular weight of 770.…”

Section: Drugmentioning

confidence: 99%

Blockade of Vascular Smooth Muscle Cell Proliferation and Intimal Thickening After Balloon Injury by the Sulfated Oligosaccharide PI-88

Francis

Parish²,

McGarry³

et al. 2003

Circulation Research

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Abstract-Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteriesthat have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (K i 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org. (Circ Res. 2003;92:e70-e77.)Key Words: phosphomannopentaose sulfate Ⅲ heparanase inhibitor Ⅲ smooth muscle cells Ⅲ neointima formation Ⅲ balloon angioplasty P hosphomannopentaose sulfate (PI-88) is a recently developed synthetic polysulfated oligosaccharide that inhibits the activity of the extracellular matrix-degrading enzyme heparanase. 1 PI-88 is a 2-kDa heparan sulfate mimetic structurally distinct from heparin, a heterogenous mixture of polysaccharide chains of varying length with a molecular weights of 3 to 30 kDa. PI-88 is also structurally and functionally different from small heparin-like polyaromatic anionic-type compounds 2 and other heparan sulfate mimetics. 1 In vivo studies have shown that PI-88 is a potent inhibitor of tumor metastasis and angiogenesis. 1 Human and mammalian toxicology studies demonstrate that PI-88 is welltolerated and has low anticoagulant activity. 3 PI-88 is currently in Phase II clinical trials to assess its therapeutic potential as an anticancer drug and is administered to patients by continuous infusion or repeated injection.Percutaneous transluminal coronary angioplasty (PTCA) is common...

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Large-scale preparation of the oligosaccharide phosphate fraction of Pichia holstii NRRL Y-2448 phosphomannan for use in the manufacture of PI-88

Cited by 57 publications

References 19 publications

A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Blockade of Vascular Smooth Muscle Cell Proliferation and Intimal Thickening After Balloon Injury by the Sulfated Oligosaccharide PI-88

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