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Glycosaminoglycans and Their Mimetics

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Diversity".

Deadline for manuscript submissions: closed (31 December 2014) | Viewed by 96782

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Dr. Vito Ferro

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School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia
Interests: carbohydrate chemistry; medicinal chemistry; heparanase inhibitors; heparan sulfate mimetics
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Dear Colleagues,

Glycosaminoglycans (GAGs) are linear, polyanionic polysaccharide chains with enormous structural diversity that are usually found attached to a protein core to form proteoglycans. The GAG chains are composed of repeating disaccharide subunits containing a uronic acid (D-GlcA or L-IdoA) or hexose (D-Gal) linked to a hexosamine (D-GlcNAc or D-GalNAc). There are five distinct types of GAGs: heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and hyaluronic acid (HA). GAGs are found on the surface of every mammalian cell and in the extracellular matrix and mediate numerous biological and pathological processes by interacting with various proteins (e.g., growth factors, cytokines, proteases, glycosidases and many others). Apart from their roles in normal growth and development, GAGs have attracted much interest because of the important roles they play in diseases such as cancer and inflammation and in infectious diseases where they are used as entry receptors by some viruses. The well-known heparin, a highly sulfated form of HS, has of course been used as an anticoagulant drug for decades. In more recent times, low molecular weight heparins (LMWH) and fondaparinux, the antithrombin-binding pentasaccharide sequence found in heparin, have complemented the use of unfractionated heparin as anticoagulant drugs.
There has been considerable interest in understanding the precise nature of the interactions between GAGs and their binding partners, in particular to define which specific sequences (or arrangement of domains) are responsible for biological activity. Advances in analytical techniques such as NMR and MS to identify GAG sequences and the synthesis of defined, homogeneous GAG oligosaccharides and glycoconjugates for use in biological studies will play an important role in advancing our understanding in this area. The development of GAG mimetics is also of great interest, particularly for the discovery of new therapeutics. GAG mimetics are compounds that block GAG–protein interactions and, by so doing, can interfere with disease processes. Activity in this area has been greatest in the field of cancer where several compounds have entered the clinic, with one of them (PI-88) in Phase III trials.
We invite our colleagues to submit research articles and comprehensive reviews addressing the above mentioned and related topics for publication in this Special Issue.

Dr. Vito Ferro
Guest Editor

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Keywords

heparan sulfate
heparin
LMWH
chondroitin sulfate
dermatan sulfate
hyaluronic acid
glycosaminoglycan
proteoglycan
heparanase

Published Papers (10 papers)

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Research

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4304 KiB

Open AccessArticle

Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis

by Jonathan S. Wall, Emily B. Martin, Tina Richey, Alan C. Stuckey, Sallie Macy, Craig Wooliver, Angela Williams, James S. Foster, Penney McWilliams-Koeppen, Ed Uberbacher, Xiaolin Cheng and Stephen J. Kennel

Molecules 2015, 20(5), 7657-7682; https://doi.org/10.3390/molecules20057657 - 27 Apr 2015

Cited by 28 | Viewed by 7663

Abstract

Amyloid is a complex pathologic matrix comprised principally of paracrystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloid diseases are rare, thus, routine diagnosis is often challenging. The glycosaminoglycans ubiquitously present in amyloid deposits are biochemically and electrochemically distinct from those found in the healthy tissues due to the high degree of sulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14, as novel agents for specifically targeting and imaging amyloid. Herein, we demonstrate that radiolabeled p5+14 effectively bound murine AA amyloid in vivo by using molecular imaging. Biotinylated peptide also reacted with the major forms of human amyloid in tissue sections as evidenced immunohistochemically. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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1057 KiB

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Modular Synthesis of Heparin-Related Tetra-, Hexa- and Octasaccharides with Differential O-6 Protections: Programming for Regiodefined 6-O-Modifications

by Marek Baráth, Steen U. Hansen, Charlotte E. Dalton, Gordon C. Jayson, Gavin J. Miller and John M. Gardiner

Molecules 2015, 20(4), 6167-6180; https://doi.org/10.3390/molecules20046167 - 09 Apr 2015

Cited by 13 | Viewed by 6143

Abstract

Heparin and heparan sulphate (H/HS) are important members of the glycosaminoglycan family of sugars that regulate a substantial number of biological processes. Such biological promiscuity is underpinned by hetereogeneity in their molecular structure. The degree of O-sulfation, particularly at the 6-position of constituent D-GlcN units, is believed to play a role in modulating the effects of such sequences. Synthetic chemistry is essential to be able to extend the diversity of HS-like fragments with defined molecular structure, and particularly to deconvolute the biological significance of modifications at O6. Here we report a synthetic approach to a small matrix of protected heparin-type oligosaccharides, containing orthogonal D-GlcN O-6 protecting groups at programmed positions along the chain, facilitating access towards programmed modifications at specific sites, relevant to sulfation or future mimetics. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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919 KiB

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Determination of the Molecular Weight of Low-Molecular-Weight Heparins by Using High-Pressure Size Exclusion Chromatography on Line with a Triple Detector Array and Conventional Methods

by Antonella Bisio, Alessandra Mantegazza, Davide Vecchietti, Donata Bensi, Alessia Coppa, Giangiacomo Torri and Sabrina Bertini

Molecules 2015, 20(3), 5085-5098; https://doi.org/10.3390/molecules20035085 - 19 Mar 2015

Cited by 26 | Viewed by 8573

Abstract

The evaluation of weight average molecular weight (Mw) and molecular weight distribution represents one of the most controversial aspects concerning the characterization of low molecular weight heparins (LMWHs). As the most commonly used method for the measurement of such parameters is high performance size exclusion chromatography (HP-SEC), the soundness of results mainly depends on the appropriate calibration of the chromatographic columns used. With the aim of meeting the requirement of proper Mw standards for LMWHs, in the present work the determination of molecular weight parameters (Mw and Mn) by HP-SEC combined with a triple detector array (TDA) was performed. The HP-SEC/TDA technique permits the evaluation of polymeric samples by exploiting the combined and simultaneous action of three on-line detectors: light scattering detectors (LALLS/RALLS); refractometer and viscometer. Three commercial LMWH samples, enoxaparin, tinzaparin and dalteparin, a γ-ray depolymerized heparin (γ-Hep) and its chromatographic fractions, and a synthetic pentasaccharide were analysed by HP-SEC/TDA. The same samples were analysed also with a conventional HP-SEC method employing refractive index (RI) and UV detectors and two different chromatographic column set, silica gel and polymeric gel columns. In both chromatographic systems, two different calibration curves were built up by using (i) γ-Hep chromatographic fractions and the corresponding Mw parameters obtained via HP-SEC/TDA; (ii) the whole γ-Hep preparation with broad Mw dispersion and the corresponding cumulative distribution function calculated via HP-SEC/TDA. In addition, also a chromatographic column calibration according to European Pharmacopoeia indication was built up. By comparing all the obtained results, some important differences among Mw and size distribution values of the three LMWHs were found with the five different calibration methods and with HP-SEC/TDA method. In particular, the detection of the lower molecular weight components turned out to be the most critical aspect. Whereas HP-SEC/TDA may underestimate species under 2 KDa when present in low concentration, other methods appeared to emphasize their content. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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7626 KiB

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Inhibition of Urinary Macromolecule Heparin on Aggregation of Nano-COM and Nano-COD Crystals

by Yan Ou, Jun-Fa Xue, Cai-Yan Tan, Bao-Song Gui, Xin-Yuan Sun and Jian-Ming Ouyang

Molecules 2015, 20(1), 1626-1642; https://doi.org/10.3390/molecules20011626 - 19 Jan 2015

Cited by 16 | Viewed by 8998

Abstract

Purpose: This research aims to study the influences of heparin (HP) on the aggregation of nano calcium oxalate monohydrate (COM) and nano calcium oxalate dihydrate (COD) with mean diameter of about 50 nm. Method: The influences of different concentrations of HP on the mean diameter and Zeta potential of nano COM and nano COD were investigated using a nanoparticle size Zeta potential analyzer. Results: HP could be adsorbed on the surface of nano COM and nano COD crystals, leading to an increase in the absolute value of Zeta potential on the crystals and an increase in the electrostatic repulsion force between crystals. Consequently, the aggregation of the crystals is reduced and the stability of the system is improved. The strong adsorption ability of HP was closely related to the -OSO₃⁻ and -COO⁻ groups contained in the HP molecules. X-ray photoelectron spectroscopy confirmed the coordination of HP with Ca²⁺ ions of COM and COD crystals. Conclusion: HP could inhibit the aggregation of nano COM and nano COD crystals and increase their stability in aqueous solution, which is conducive in inhibiting the formation of calcium oxalate stones. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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1465 KiB

Open AccessArticle

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

by Rami A. Al-Horani, Rajesh Karuturi, Domonique T. White and Umesh R. Desai

Molecules 2015, 20(1), 608-624; https://doi.org/10.3390/molecules20010608 - 05 Jan 2015

Cited by 23 | Viewed by 6756

Abstract

Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC₅₀ = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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Review

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685 KiB

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Discrepancies in Composition and Biological Effects of Different Formulations of Chondroitin Sulfate

by Johanne Martel-Pelletier, Aina Farran, Eulàlia Montell, Josep Vergés and Jean-Pierre Pelletier

Molecules 2015, 20(3), 4277-4289; https://doi.org/10.3390/molecules20034277 - 06 Mar 2015

Cited by 84 | Viewed by 12680

Abstract

Osteoarthritis is a common, progressive joint disease, and treatments generally aim for symptomatic improvement. However, SYmptomatic Slow-Acting Drugs in Osteoarthritis (SYSADOAs) not only reduce joint pain, but slow structural disease progression. One such agent is chondroitin sulfate—a complex, heterogeneous polysaccharide. It is extracted from various animal cartilages, thus has a wide range of molecular weights and different amounts and patterns of sulfation. Chondroitin sulfate has an excellent safety profile, and although various meta-analyses have concluded that it has a beneficial effect on symptoms and structure, others have concluded little or no benefit. This may be due, at least partly, to variations in the quality of the chondroitin sulfate used for a particular study. Chondroitin sulfate is available as pharmaceutical- and nutraceutical-grade products, and the latter have great variations in preparation, composition, purity and effects. Moreover, some products contain a negligible amount of chondroitin sulfate and among samples with reasonable amounts, in vitro testing showed widely varying effects. Of importance, although some showed anti-inflammatory effects, others demonstrated weak effects, and some instances were even pro-inflammatory. This could be related to contaminants, which depend on the origin, production and purification process. It is therefore vitally important that only pharmaceutical-grade chondroitin sulfate be used for treating osteoarthritis patients. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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866 KiB

Open AccessReview

Can We Produce Heparin/Heparan Sulfate Biomimetics Using “Mother-Nature” as the Gold Standard?

by Brooke L. Farrugia, Megan S. Lord, James Melrose and John M. Whitelock

Molecules 2015, 20(3), 4254-4276; https://doi.org/10.3390/molecules20034254 - 05 Mar 2015

Cited by 24 | Viewed by 12948

Abstract

Heparan sulfate (HS) and heparin are glycosaminoglycans (GAGs) that are heterogeneous in nature, not only due to differing disaccharide combinations, but also their sulfate modifications. HS is well known for its interactions with various growth factors and cytokines; and heparin for its clinical use as an anticoagulant. Due to their potential use in tissue regeneration; and the recent adverse events due to contamination of heparin; there is an increased surge to produce these GAGs on a commercial scale. The production of HS from natural sources is limited so strategies are being explored to be biomimetically produced via chemical; chemoenzymatic synthesis methods and through the recombinant expression of proteoglycans. This review details the most recent advances in the field of HS/heparin synthesis for the production of low molecular weight heparin (LMWH) and as a tool further our understanding of the interactions that occur between GAGs and growth factors and cytokines involved in tissue development and repair. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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Glycosaminoglycans and Glycomimetics in the Central Nervous System

by Dáire Rowlands, Kazuyuki Sugahara and Jessica C. F. Kwok

Molecules 2015, 20(3), 3527-3548; https://doi.org/10.3390/molecules20033527 - 19 Feb 2015

Cited by 28 | Viewed by 8676

Abstract

With recent advances in the construction of synthetic glycans, selective targeting of the extracellular matrix (ECM) as a potential treatment for a wide range of diseases has become increasingly popular. The use of compounds that mimic the structure or bioactive function of carbohydrate structures has been termed glycomimetics. These compounds are mostly synthetic glycans or glycan-binding constructs which manipulate cellular interactions. Glycosaminoglycans (GAGs) are major components of the ECM and exist as a diverse array of differentially sulphated disaccharide units. In the central nervous system (CNS), they are expressed by both neurons and glia and are crucial for brain development and brain homeostasis. The inherent diversity of GAGs make them an essential biological tool for regulating a complex range of cellular processes such as plasticity, cell interactions and inflammation. They are also involved in the pathologies of various neurological disorders, such as glial scar formation and psychiatric illnesses. It is this diversity of functions and potential for selective interventions which makes GAGs a tempting target. In this review, we shall describe the molecular make-up of GAGs and their incorporation into the ECM of the CNS. We shall highlight the different glycomimetic strategies that are currently being used in the nervous system. Finally, we shall discuss some possible targets in neurological disorders that may be addressed using glycomimetics. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

797 KiB

Open AccessReview

Diversity of Heparan Sulfate and HSV Entry: Basic Understanding and Treatment Strategies

by Vaibhav Tiwari, Morgan S. Tarbutton and Deepak Shukla

Molecules 2015, 20(2), 2707-2727; https://doi.org/10.3390/molecules20022707 - 05 Feb 2015

Cited by 41 | Viewed by 10202

Abstract

A modified form of heparan sulfate (HS) known as 3-O-sulfated heparan sulfate (3-OS HS) generates fusion receptor for herpes simplex virus (HSV) entry and spread. Primary cultures of corneal fibroblasts derived from human eye donors have shown the clinical significance of this receptor during HSV corneal infection. 3-OS HS- is a product of a rare enzymatic modification at C3 position of glucosamine residue which is catalyzed by 3-O-sulfotransferases (3-OSTs) enzymes. From humans to zebrafish, the 3-OST enzymes are highly conserved and widely expressed in cells and tissues. There are multiple forms of 3-OSTs each producing unique subset of sulfated HS making it chemically diverse and heterogeneous. HSV infection of cells or zebrafish can be used as a unique tool to understand the structural-functional activities of HS and 3-OS HS and likewise, the infection can be used as a functional assay to screen phage display libraries for identifying HS and 3-OS HS binding peptides or small molecule inhibitors. Using this approach over 200 unique 12-mer HS and 3-OS HS recognizing peptides were isolated and characterized against HSV corneal infection where 3-OS HS is known to be a key receptor. In this review we discuss emerging role of 3-OS HS based therapeutic strategies in preventing viral infection and tissue damage. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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1128 KiB

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The Effect of Glycosaminoglycans (GAGs) on Amyloid Aggregation and Toxicity

by Clara Iannuzzi, Gaetano Irace and Ivana Sirangelo

Molecules 2015, 20(2), 2510-2528; https://doi.org/10.3390/molecules20022510 - 02 Feb 2015

Cited by 85 | Viewed by 12302

Abstract

Amyloidosis is a protein folding disorder in which normally soluble proteins are deposited extracellularly as insoluble fibrils, impairing tissue structure and function. Charged polyelectrolytes such as glycosaminoglycans (GAGs) are frequently found associated with the proteinaceous deposits in tissues of patients affected by amyloid diseases. Experimental evidence indicate that they can play an active role in favoring amyloid fibril formation and stabilization. Binding of GAGs to amyloid fibrils occurs mainly through electrostatic interactions involving the negative polyelectrolyte charges and positively charged side chains residues of aggregating protein. Similarly to catalyst for reactions, GAGs favor aggregation, nucleation and amyloid fibril formation functioning as a structural templates for the self-assembly of highly cytotoxic oligomeric precursors, rich in β-sheets, into harmless amyloid fibrils. Moreover, the GAGs amyloid promoting activity can be facilitated through specific interactions via consensus binding sites between amyloid polypeptide and GAGs molecules. We review the effect of GAGs on amyloid deposition as well as proteins not strictly related to diseases. In addition, we consider the potential of the GAGs therapy in amyloidosis. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)

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