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Emerging Frontiers in Glycosaminoglycans and Mimetics

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Published Papers

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

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 25197

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Special Issue Editors

Dr. Giangiacomo Torri

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Guest Editor

Carbohydrate Sciences Department, Ronzoni Institute, Milan, Italy
Interests: heparin; LMWH; glycosaminoglycan; protein–carbohydrate interaction; glycol-split heparins; heparin mimetics; nanoparticles engineered with heparin; polysaccharides and derivatives; structure–activity relationship; oligosaccharide analysis; nuclear magnetic resonance/PCA; mass spectrometry
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jawed Fareed

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Guest Editor

Loyola University Medical Center, Maywood, USA
Interests: athophysiologic characterization of thrombotic and cardiovascular agents; development of new antithrombotic drugs; pharmacologic differentiation of low molecular weight heparins; development of heparinomimetic drugs; molecular modeling of thrombogenesis using simulated systems; development of animal models of thrombotic and ischemic disorders
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Job Harenberg

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Guest Editor

Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer Ufer 1-3, D-68167 Mannheim, Germany
Interests: heparin; glycosaminoglycans; anticoagulant activity; anticoagulant methods; protein interactions; biological activities; clinical applications

Special Issue Information

Dear Colleagues,

In the past 35 years, we have witnessed important developments in the knowledge of glycosaminoglycans (GAGs), among which the heparin and heparin like compounds have received the most attention. Researchers have clarified relevant scientific aspects and have led to evolutions in the clinical use of heparin, especially due to the introduction of various low-molecular weight heparins. Currently, the research is increasingly focusing on the pleiotropic clinical potentials of GAGs, such as their antitumoral, anti-metastatic, and antiviral activities. Attention is also given to the structural differentiation occurring between molecules extracted from different animal species and tissues, while the explanation of these differences is still delayed. Studies in the field of the biotechnological synthesis routes, GAG derivatives and mimetics, functionalized materials, and nanostructures are also under development.This initiative follows the collection of 21 articles published by Molecules in the Special Issue “Looking Forward to the Future of Heparin: New Sources, Developments and Applications” published on the anniversary of the heparin centenary.Given the interest raised by that Issue, it is considered appropriate to re-propose the initiative, inviting the researchers involved in this sector to participate, in particular exhorting those who participated in the Symposium of Glycosaminoglycans, held annually at the German–Italian Centre for European Excellence, Villa Vigoni, Menaggio, Lake Como, Italy.International expert groups are invited to contribute to this new initiative with actual and emerging topics of interest in the fields of chemistry, biochemistry, biology, pharmacology, regulatory rules, and clinical applications of heparin and other glycosaminoglycans. Both basic and applied aspects will be included in the collection.

Dr. Giangiacomo Torri
Prof. Jawed Fareed
Prof. Job Harenberg
Guest Editors

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Keywords

heparin
structure–function relationship
heparin-like molecules
heparinases and heparanase
pleiotropic biological effects
chemical and analytical methods
clinical application of heparin and related compounds

Published Papers (6 papers)

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Research

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16 pages, 3274 KiB

Open AccessArticle

Glycosaminoglycans as Tools to Decipher the Platelet Tumor Cell Interaction: A Focus on P-Selectin

by Svenja Schwarz, Lukas Maria Gockel, Annamaria Naggi, Uri Barash, Martina Gobec, Gerd Bendas and Martin Schlesinger

Molecules 2020, 25(5), 1039; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25051039 - 26 Feb 2020

Cited by 25 | Viewed by 3157

Abstract

Tumor cell–platelet interactions are regarded as an initial crucial step in hematogenous metastasis. Platelets protect tumor cells from immune surveillance in the blood, mediate vascular arrest, facilitate tumor extravasation, growth, and finally angiogenesis in the metastatic foci. Tumor cells aggregate platelets in the bloodstream by activation of the plasmatic coagulation cascade and by direct contact formation. Antimetastatic activities of unfractionated or low molecular weight heparin (UFH/LMWH) can undoubtedly be related to attenuated platelet activation, but molecular mechanisms and contribution of contact formation vs. coagulation remain to be elucidated. Using a set of non-anticoagulant heparin derivatives varying in size or degree of sulfation as compared with UFH, we provide insight into the relevance of contact formation for platelet activation. Light transmission aggregometry and ATP release assays confirmed that only those heparin derivatives with P-selectin blocking capacities were able to attenuate breast cancer cell-induced platelet activation, while pentasaccharide fondaparinux was without effects. Furthermore, a role of P-selectin in platelet activation and signaling could be confirmed by proteome profiler arrays detecting platelet kinases. In this study, we demonstrate that heparin blocks tumor cell-induced coagulation. Moreover, we identify platelet P-selectin, which obviously acts as molecular switch and controls aggregation and secretion of procoagulant platelets. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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15 pages, 1872 KiB

Open AccessFeature PaperArticle

Heparanase as an Additional Tool for Detecting Structural Peculiarities of Heparin Oligosaccharides

by Anna Alekseeva, Elena Urso, Giulia Mazzini and Annamaria Naggi

Molecules 2019, 24(23), 4403; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234403 - 02 Dec 2019

Cited by 8 | Viewed by 2748

Abstract

Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and discovery of novel structural peculiarities are crucial. Effective strategies for monitoring manufacturing processes and assessment of more restrictive specifications, as imposed by the current regulatory agencies, need to be developed. Hereby, we apply an efficient heparanase-based strategy to assert the structure of two major isomeric octasaccharides of dalteparin and investigate the tetrasaccharides arising from antithrombin binding region (ATBR) of bovine mucosal heparin. Heparanase, especially when combined with other sample preparation methods (e.g., size exclusion, affinity chromatography, heparinase depolymerization), was shown to be a powerful tool providing relevant information about heparin structural peculiarities. The applied approach provided direct evidence that oligomers bearing glucuronic acid–glucosamine-3-O-sulfate at their nonreducing end represent an important structural signature of dalteparin. When extended to ATBR-related tetramers of bovine heparin, the heparanase-based approach allowed for elucidation of the structure of minor sequences that have not been reported yet. The obtained results are of high importance in the view of the growing interest of regulatory agencies and manufacturers in the development of low-molecular-weight heparin generics as well as bovine heparin as alternative source. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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18 pages, 3964 KiB

Open AccessArticle

Crude Heparin Preparations Unveil the Presence of Structurally Diverse Oversulfated Contaminants

by Aline Mendes, Maria C. Z. Meneghetti, Marcelly Valle Palladino, Giselle Zenker Justo, Guilherme L. Sassaki, Jawed Fareed, Marcelo A. Lima and Helena B. Nader

Molecules 2019, 24(16), 2988; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24162988 - 17 Aug 2019

Cited by 5 | Viewed by 4387

Abstract

Nowadays, pharmaceutical heparin is purified from porcine and bovine intestinal mucosa. In the past decade there has been an ongoing concern about the safety of heparin, since in 2008, adverse effects associated with the presence of an oversulfated chondroitin sulfate (OSCS) were observed in preparations of pharmaceutical porcine heparin, which led to the death of patients, causing a global public health crisis. However, it has not been clarified whether OSCS has been added to the purified heparin preparation, or whether it has already been introduced during the production of the raw heparin. Using a combination of different analytical methods, we investigate both crude and final heparin products and we are able to demonstrate that the sulfated contaminants are intentionally introduced in the initial steps of heparin preparation. Furthermore, the results show that the oversulfated compounds are not structurally homogeneous. In addition, we show that these contaminants are able to bind to cells in using well known heparin binding sites. Together, the data highlights the importance of heparin quality control even at the initial stages of its production. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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Review

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22 pages, 919 KiB

Open AccessReview

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

by Noemi Veraldi, Nawel Zouggari and Ariane de Agostini

Molecules 2020, 25(2), 390; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020390 - 17 Jan 2020

Cited by 8 | Viewed by 4347

Abstract

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. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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25 pages, 3765 KiB

Open AccessReview

Heparinoid Complex-Based Heparin-Binding Cytokines and Cell Delivery Carriers

by Masayuki Ishihara, Shingo Nakamura, Yoko Sato, Tomohiro Takayama, Koichi Fukuda, Masanori Fujita, Kaoru Murakami and Hidetaka Yokoe

Molecules 2019, 24(24), 4630; https://doi.org/10.3390/molecules24244630 - 17 Dec 2019

Cited by 8 | Viewed by 5316

Abstract

Heparinoid is the generic term that is used for heparin, heparan sulfate (HS), and heparin-like molecules of animal or plant origin and synthetic derivatives of sulfated polysaccharides. Various biological activities of heparin/HS are attributed to their specific interaction and regulation with various heparin-binding cytokines, antithrombin (AT), and extracellular matrix (ECM) biomolecules. Specific domains with distinct saccharide sequences in heparin/HS mediate these interactions are mediated and require different highly sulfated saccharide sequences with different combinations of sulfated groups. Multivalent and cluster effects of the specific sulfated sequences in heparinoids are also important factors that control their interactions and biological activities. This review provides an overview of heparinoid-based biomaterials that offer novel means of engineering of various heparin-binding cytokine-delivery systems for biomedical applications and it focuses on our original studies on non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) and polyelectrolyte complex-nano/microparticles (N/MPs), in addition to heparin-coating devices. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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33 pages, 3219 KiB

Open AccessReview

Galactosaminoglycans: Medical Applications and Drawbacks

by Vitor H. Pomin, William P. Vignovich, Alysia V. Gonzales, Ariana A. Vasconcelos and Barbara Mulloy

Molecules 2019, 24(15), 2803; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24152803 - 01 Aug 2019

Cited by 31 | Viewed by 4755

Abstract

Galactosaminoglycans (GalAGs) are sulfated glycans composed of alternating N-acetylgalactosamine and uronic acid units. Uronic acid epimerization, sulfation patterns and fucosylation are modifications observed on these molecules. GalAGs have been extensively studied and exploited because of their multiple biomedical functions. Chondroitin sulfates (CSs), the main representative family of GalAGs, have been used in alternative therapy of joint pain/inflammation and osteoarthritis. The relatively novel fucosylated chondroitin sulfate (FCS), commonly found in sea cucumbers, has been screened in multiple systems in addition to its widely studied anticoagulant action. Biomedical properties of GalAGs are directly dependent on the sugar composition, presence or lack of fucose branches, as well as sulfation patterns. Although research interest in GalAGs has increased considerably over the three last decades, perhaps motivated by the parallel progress of glycomics, serious questions concerning the effectiveness and potential side effects of GalAGs have recently been raised. Doubts have centered particularly on the beneficial functions of CS-based therapeutic supplements and the potential harmful effects of FCS as similarly observed for oversulfated chondroitin sulfate, as a contaminant of heparin. Unexpected components were also detected in CS-based pharmaceutical preparations. This review therefore aims to offer a discussion on (1) the current and potential therapeutic applications of GalAGs, including those of unique features extracted from marine sources, and (2) the potential drawbacks of this class of molecules when applied to medicine. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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