Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Lim, Teck Chuan; Cai, Shuting; Huber, Roland G.; Bond, Peter J.; Chia, Priscilla Xian Siew; Khou, Siv Ly; Gao, Shujun; Lee, Su Seong; Lee, Song-Gil

doi:10.1039/c8sc02303d

Cited by 10 publications

(8 citation statements)

References 37 publications

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“…This unexpected result could enable profiling of an unknown effect of minor sulfated-disaccharides along the CS backbone in the arrangement of sulfates on the helical 3-D structure of polysaccharides. Indeed, the CD spectrum showed the negative band at 210 nm that has previously been described for polysaccharides rich in α-helical content [ 32 ], including those with rare sulfate distributions ( Figure 7 b).…”

Section: Resultssupporting

confidence: 57%

“…A similar trend was observed with CS-11, a polysaccharide obtained by partial sulfation (~50%) at the C-6 position of GalNAc moieties of CS-14. Strikingly, the binding affinity of this polysaccharide to FGF-2 ( k D1 = 1.33 µM, k D2 = 4.75 nM) ( Table 4 , entry 8) was even higher than CS-14, although a slight increase in zeta potential was observed (−31.0 vs. −35.2 mV), corroborating again the importance of molecular architecture in these binding processes [ 32 ].…”

Section: Resultsmentioning

confidence: 68%

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Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of Their Biological Functions

Vessella

Vázquez²,

Valcárcel³

et al. 2021

Polymers

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Controlling chondroitin sulfates (CSs) biological functions to exploit their interesting potential biomedical applications requires a comprehensive understanding of how the specific sulfate distribution along the polysaccharide backbone can impact in their biological activities, a still challenging issue. To this aim, herein, we have applied an “holistic approach” recently developed by us to look globally how a specific sulfate distribution within CS disaccharide epitopes can direct the binding of these polysaccharides to growth factors. To do this, we have analyzed several polysaccharides of marine origin and semi-synthetic polysaccharides, the latter to isolate the structure-activity relationships of their rare, and even unnatural, sulfated disaccharide epitopes. SPR studies revealed that all the tested polysaccharides bind to FGF-2 (with exception of CS-8, CS-12 and CS-13) according to a model in which the CSs first form a weak complex with the protein, which is followed by maturation to tight binding with kD ranging affinities from ~1.31 μM to 130 μM for the first step and from ~3.88 μM to 1.8 nM for the second one. These binding capacities are, interestingly, related with the surface charge of the 3D-structure that is modulated by the particular sulfate distribution within the disaccharide repeating-units.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 68%

Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of Their Biological Functions

Vessella

Vázquez²,

Valcárcel³

et al. 2021

Polymers

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“…Another recent study highlighted the use of polyproline-based GAG mimetics (PGMs) that recapitulate key structural features of GAGs, including periodicity, the length of repeating units, turnability, and helicity, as shown through molecular dynamics simulations [107]. One of the synthesized PGMs, {Z} 12 (Figure 4D), inhibited the interaction of CS-E with P-selectin, which is implicated in metastasis and inflammation.…”

Section: Gag Mimeticsmentioning

confidence: 99%

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

Morla

2019

IJMS

173

125

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Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed with encouraging results in animal models and clinical trials, showcasing their potential for development as therapeutics. In this review, the role GAGs play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed.

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“…Lim and collaborators developed saccharide-free polyproline-based GAG mimetics (PGMs) that recapitulate key GAG structural features, notably the sized repeating units, periodicity, and helicity. GAG activities were also maintained, indeed PGMs effectively inhibited chondroitin sulfate-E binding to P-selectin which is implicated in metastasis, thrombosis and inflammation and successfully attenuate hematogenous metastasis in vivo in mice model as effectively as heparin and tinzaparin without any adverse effects on mice model, suggesting its safe use in vivo [183].…”

Section: Targeting the Tumor Microenvironmentmentioning

confidence: 93%

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

2020

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This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

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Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Abstract: We report a new class of saccharide-free glycosaminoglycan (GAG) mimetics where polyproline imparts facilely-made sulfation patterns with GAG-like structure, function and tunability.

Cited by 10 publications

References 37 publications

Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of Their Biological Functions

Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of Their Biological Functions

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

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