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Oligosaccharides and Glyco-Conjugates

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

Deadline for manuscript submissions: closed (31 March 2014) | Viewed by 97053

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Prof. Dr. Marco Terreni

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Department of Drug Sciences, School of Pharmacy, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
Interests: syndetic organic chemistry; medicinal chemistry; chemical biology; protein engineering; biocatalysis
Special Issues, Collections and Topics in MDPI journals

Dr. Caterina Temporini

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Department of Drug Sciences, School of Pharmacy, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
Interests: analytical chemistry; medicinal chemistry; protein engeenering

Special Issue Information

Dear Colleagues,

Carbohydrates occur naturally as oligo- and polysaccharides and are often coupled to peptides. proteins and lipids. In particular, oligosaccharides and glyco-conjugates have key roles in a broad range of biological processes. In many cases, changes in the sugar structures can affect the biological properties of the parent compounds. Furthermore, functional properties of drugs such as solubility, pharmacokinetics or pharmacodynamics can be enhanced by the incorporation of carbohydrate moieties into the molecules.
Methods for synthesizing these molecules have, therefore, acquired immense importance, because it is not easy to isolate sufficient amounts of acceptable pure product from natural sources.
On the other hand, the structure of therapeutic bio-products is critically important for their efficacy and safety, and the ability to characterize it at various levels (from sequence to conformation) is critical not only at the quality control stage, but also throughout the discovery and design stages because these structural information enable to optimize and enhance their therapeutic profile in a rational fashion.
Many analytical technologies have been deeply improved in the last years for determining the exact structure of complex oligosaccharides and glyco-conjugates For example Liquid Chromatography coupled to mass spectrometry (LC-MS) offers a variety of approaches to study structure and behaviour of complex protein drugs and has already become a default tool for characterizing the covalent structure, including sequence and post-translational modifications such as glycosylation which is the most common PTM in currently developed biopharmaceuticals.
Research papers dealing with the study and development of new compounds as well as new synthetic approaches, including new enzymatic or chemoenzymatic methods, new methods for analytical and biological characterization of oligosaccharides and glyco-conjugates, are welcomed for inclusion into this Special Issue of Molecules. Review articles, particularly those dealing with retrospective analyses of prior successes in the discovery and/or development of new drugs based on oligosaccharides and glyco-conjugates, are also welcomed for inclusion.

Prof. Dr. Marco Terreni
Dr. Caterina Temporini
Guest Editors

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Keywords

oligosaccharides
glycopeptides
glycoproteins
glycolipids
synthesis
analysis
structure characterization
biological activity
structure based drug design
drug discovery and development

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Published Papers (12 papers)

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Research

1919 KiB

Open AccessArticle

Synthesis and Molecular Structure of the 5-Methoxycarbonylpentyl α-Glycoside of the Upstream, Terminal Moiety of the O-Specific Polysaccharide of Vibrio cholerae O1, Serotype Inaba

by Peng Xu, Edwin D. Stevens, Alfred D. French and Pavol Kováč

Molecules 2015, 20(2), 2892-2902; https://doi.org/10.3390/molecules20022892 - 11 Feb 2015

Cited by 2 | Viewed by 5310

Abstract

The trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed reaction of methyl 6-hydroxyhexanoate with 3-O-benzyl-4-(2,4-di-O-acetyl-3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-2-O-levulinoyl-α-d-mannopyranosyl trichloroacetimidate followed by a two-step deprotection (hydrogenolysis over Pd/C catalyst and Zemplén deacylation, to simultaneously remove the acetyl and levulinoyl groups) gave 5-(methoxycarbonyl)pentyl 4-(3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-α-D-mannopyranoside. The structure of the latter, for which crystals were obtained in the analytically pure state for the first time, followed from its NMR and high-resolution mass spectra and was confirmed by X-ray crystallography. The molecule has two approximately linear components; a line through the aglycon intersects a line through the mannosyl and tetronylamido groups at 120°. The crystal packing separates the aglycon groups from the tetronylamido and mannosyl groups, with only C-H…O hydrogen bonding among the aglycon groups and N-H…O, O-H…O and C-H…O links among the tetronylamido and mannosyl groups. A carbonyl oxygen atom accepts the strongest O-H…O hydrogen bond and two strong C-H…O hydrogen bonds. The geometric properties were compared with those of related molecules. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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439 KiB

Open AccessArticle

A Combinatorial Approach to Biophysically Characterise Chemokine-Glycan Binding Affinities for Drug Development

by Tanja Gerlza, Bianca Hecher, Dalibor Jeremic, Thomas Fuchs, Martha Gschwandtner, Angelika Falsone, Bernd Gesslbauer and Andreas J. Kungl

Molecules 2014, 19(7), 10618-10634; https://doi.org/10.3390/molecules190710618 - 22 Jul 2014

Cited by 35 | Viewed by 7470

Abstract

Chemokine binding to glycosaminoglycans (GAGs) is recognised to be an important step in inflammation and other pathological disorders like tumor growth and metastasis. Although different ways and strategies to interfere with these interactions are being pursued, no major breakthrough in the development of glycan-targeting drugs has been reported so far. We have engineered CXCL8 towards a dominant-negative form of this chemokine (dnCXCL8) which was shown to be highly active in various inflammatory animal models due to its inability to bind/activate the cognate CXCL8 GPC receptors on neutrophils in combination with its significantly increased GAG-binding affinity [1]. For the development of GAG-targeting chemokine-based biopharmaceuticals, we have established a repertoire of methods which allow the quantification of protein-GAG interactions. Isothermal fluorescence titration (IFT), surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and a novel ELISA-like competition assay (ELICO) have been used to determine K_d and IC₅₀ values for CXCL8 and dnCXCL8 interacting with heparin and heparan sulfate (HS), the proto-typical members of the GAG family. Although the different methods gave different absolute affinities for the four protein-ligand pairs, the relative increase in GAG-binding affinity of dnCXCL8 compared to the wild type chemokine was found by all methods. In combination, these biophysical methods allow to discriminate between unspecific and specific protein-GAG interactions. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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572 KiB

Open AccessArticle

Relative Quantitation of Glycopeptides Based on Stable Isotope Labeling Using MALDI-TOF MS

by Masaki Kurogochi and Junko Amano

Molecules 2014, 19(7), 9944-9961; https://doi.org/10.3390/molecules19079944 - 9 Jul 2014

Cited by 21 | Viewed by 8419

Abstract

We have developed an effective, sensitive method for quantitative glycopeptide profiling using stable isotope labeling and MALDI-TOF mass spectrometry (MS). In this study, we synthesized benzoic acid-d0 N-succinimidyl ester (BzOSu) and benzoic acid-d5 N-succinimidyl ester (d-BzOSu) as light and heavy isotope reagents for stable isotope quantification for the comparative analysis of glycopeptides. Using this approach provided enhanced ionization efficiency in both positive and negative modes by MALDI-TOF MS. These reagents were quantitatively reacted with glycopeptides from human serum IgG (hIgG) at a wide range of concentrations; the labeling efficiency of the glycopeptides showed high reproducibility and a good calibration curve was obtained. To demonstrate the practical utility of this approach, we characterized the structures of glycopeptides from hIgG and from IgG1 produced by myeloma plasma. The glycopeptides were quantitatively analyzed by mixing Bz-labeled IgG1 glycopeptides with d-Bz-labeled hIgG glycopeptides. Glycan structural identification of the hIgG glycopeptides was demonstrated by combining the highly specific recognition of endo-β-N-acetyl glucosaminidases from Streptococcus pyogenes (endoS) or from Streptococcus pneumoniae (endo-D) with MALDI-TOF MS analysis. The obtained data revealed the glycan profile and the ratio of glycan structural isomers containing a galactosylated extension on IgG1, IgG2 and IgG3 glycopetides. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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2269 KiB

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Characterization of Intact Neo-Glycoproteins by Hydrophilic Interaction Liquid Chromatography

by Alice Pedrali, Sara Tengattini, Giorgio Marrubini, Teodora Bavaro, Petrus Hemström, Gabriella Massolini, Marco Terreni and Caterina Temporini

Molecules 2014, 19(7), 9070-9088; https://doi.org/10.3390/molecules19079070 - 30 Jun 2014

Cited by 34 | Viewed by 7408

Abstract

In this study, an HPLC HILIC-UV method was developed for the analysis of intact neo-glycoproteins. During method development the experimental conditions evaluated involved different HILIC columns (TSKgel Amide-80 and ZIC-pHILIC), and water-acetonitrile mixtures containing various types of acids and salts. The final selected method was based on a TSKgel Amide-80 column and a mobile phase composed of acetonitrile and water both containing 10 mM HClO₄. The influence of temperature and sample preparation on the chromatographic performances of the HILIC method was also investigated. The method was applied to the separation of neo-glycoproteins prepared starting from the model protein RNase A by chemical conjugation of different glycans. Using the method here reported it was possible to monitor by UV detection the glycosylation reaction and assess the distribution of neo-glycoprotein isoforms without laborious sample workup prior to analysis. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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1822 KiB

Open AccessArticle

High-Throughput Assay of Levansucrase Variants in Search of Feasible Catalysts for the Synthesis of Fructooligosaccharides and Levan

by Karin Mardo, Triinu Visnapuu, Maria Gromkova, Anneli Aasamets, Katrin Viigand, Heiki Vija and Tiina Alamäe

Molecules 2014, 19(6), 8434-8455; https://doi.org/10.3390/molecules19068434 - 20 Jun 2014

Cited by 25 | Viewed by 8566

Abstract

Bacterial levansucrases polymerize fructose residues of sucrose to β-2,6 linked fructans—fructooligosaccharides (FOS) and levan. While β-2,1-linked FOS are widely recognized as prebiotics, the health-related effects of β-2,6 linked FOS are scarcely studied as they are not commercially available. Levansucrase Lsc3 (Lsc-3) of Pseudomonas syringae pv. tomato has very high catalytic activity and stability making it a promising biotechnological catalyst for FOS and levan synthesis. In this study we evaluate feasibility of several high-throughput methods for screening and preliminary characterization of levansucrases using 36 Lsc3 mutants as a test panel. Heterologously expressed and purified His-tagged levansucrase variants were studied for: (1) sucrose-splitting activity; (2) FOS production; (3) ability and kinetics of levan synthesis; (4) thermostability in a Thermofluor assay. Importantly, we show that sucrose-splitting activity as well as the ability to produce FOS can both be evaluated using permeabilized levansucrase-expressing E. coli transformants as catalysts. For the first time we demonstrate the key importance of Trp109, His113, Glu146 and Glu236 for the catalysis of Lsc3. Cost-effective and high-throughput methods presented here are applicable not only in the levansucrase assay, but have a potential to be adapted for high-throughput (automated) study of other enzymes. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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1475 KiB

Open AccessArticle

FACE Analysis as a Fast and Reliable Methodology to Monitor the Sulfation and Total Amount of Chondroitin Sulfate in Biological Samples of Clinical Importance

by Evgenia Karousou, Athanasia Asimakopoulou, Luca Monti, Vassiliki Zafeiropoulou, Nikos Afratis, Panagiotis Gartaganis, Antonio Rossi, Alberto Passi and Nikos K. Karamanos

Molecules 2014, 19(6), 7959-7980; https://doi.org/10.3390/molecules19067959 - 12 Jun 2014

Cited by 11 | Viewed by 7385

Abstract

Glycosaminoglycans (GAGs) due to their hydrophilic character and high anionic charge densities play important roles in various (patho)physiological processes. The identification and quantification of GAGs in biological samples and tissues could be useful prognostic and diagnostic tools in pathological conditions. Despite the noteworthy progress in the development of sensitive and accurate methodologies for the determination of GAGs, there is a significant lack in methodologies regarding sample preparation and reliable fast analysis methods enabling the simultaneous analysis of several biological samples. In this report, developed protocols for the isolation of GAGs in biological samples were applied to analyze various sulfated chondroitin sulfate- and hyaluronan-derived disaccharides using fluorophore-assisted carbohydrate electrophoresis (FACE). Applications to biologic samples of clinical importance include blood serum, lens capsule tissue and urine. The sample preparation protocol followed by FACE analysis allows quantification with an optimal linearity over the concentration range 1.0–220.0 µg/mL, affording a limit of quantitation of 50 ng of disaccharides. Validation of FACE results was performed by capillary electrophoresis and high performance liquid chromatography techniques. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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279 KiB

Open AccessArticle

Direct 2,3-O-Isopropylidenation of α-D-Mannopyranosides and the Preparation of 3,6-Branched Mannose Trisaccharides

by Rui Jiang, Guanghui Zong, Xiaomei Liang, Shuhui Jin, Jianjun Zhang and Daoquan Wang

Molecules 2014, 19(5), 6683-6693; https://doi.org/10.3390/molecules19056683 - 22 May 2014

Cited by 7 | Viewed by 7909

Abstract

A highly efficient, regioselective method for the direct 2,3-O-isopropylidenation of α-D-mannopyranosides is reported. Treatment of various α-D-mannopyranosides with 0.12 equiv of the TsOH·H₂O and 2-methoxypropene at 70 °C gave 2,3-O-isopropylidene-α-D-mannopyranosides directly in 80%~90% yields. Based on this method, a 3,6-branched α-D-mannosyl trisaccharide was prepared in 50.4% total yield using p-nitrophenyl 2,3-O-isopropylidene-α-D-mannopyranoside as the starting material. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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1346 KiB

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Conformational Characterization of Ipomotaosides and Their Recognition by COX-1 and 2

by Pablo R. Arantes, Liana G. Sachett, Cedric S. Graebin and Hugo Verli

Molecules 2014, 19(4), 5421-5433; https://doi.org/10.3390/molecules19045421 - 24 Apr 2014

Cited by 5 | Viewed by 5997

Abstract

The aerial parts of Ipomoea batatas are described herein to produce four new resin glycosides, designated as ipomotaosides A, B, C, and D. Ipomotaoside A was found to present inhibitory activity on both cyclooxygenases. However, the conformational elucidation of these molecules may be difficult due to their high flexibility. In this context, the current work presents a conformational characterization of ipomotaosides A–D in aqueous and nonaqueous solvents. The employed protocol includes metadynamics evaluation and unrestrained molecular dynamics simulations (MD). The obtained data provided structural models for the ipomotaosides in good agreement with previous ROESY distances measured in pyridine. Accordingly, the most abundant conformation of ipomotaoside A in solution was employed in flexible docking studies, providing a structural basis for the compound’s inhibition of COX enzymes. The so-obtained complex supports resin glycosides’ role as original scaffolds for future studies, aiming at structural optimization and development of potential new anti-inflammatory agents. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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812 KiB

Open AccessArticle

MALDI-TOF MS Analysis of Cellodextrins and Xylo-oligosaccharides Produced by Hindgut Homogenates of Reticulitermes santonensis

by Catherine Brasseur, Julien Bauwens, Cédric Tarayre, Christel Mattéotti, Philippe Thonart, Jacqueline Destain, Frédéric Francis, Eric Haubruge, Daniel Portetelle, Micheline Vandenbol, Jean-François Focant and Edwin De Pauw

Molecules 2014, 19(4), 4578-4594; https://doi.org/10.3390/molecules19044578 - 11 Apr 2014

Cited by 15 | Viewed by 8332

Abstract

Hindgut homogenates of the termite Reticulitermes santonensis were incubated with carboxymethyl cellulose (CMC), crystalline celluloses or xylan substrates. Hydrolysates were analyzed with matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry (MALDI-TOF MS). The method was first set up using acid hydrolysis analysis to characterize non-enzymatic profiles. Commercial enzymes of Trichoderma reesei or T. longibrachiatum were also tested to validate the enzymatic hydrolysis analysis. For CMC hydrolysis, data processing and visual display were optimized to obtain comprehensive profiles and allow rapid comparison and evaluation of enzymatic selectivity, according to the number of substituents of each hydrolysis product. Oligosaccharides with degrees of polymerization (DPs) ranging from three to 12 were measured from CMC and the enzymatic selectivity was demonstrated. Neutral and acidic xylo-oligosaccharides with DPs ranging from three to 11 were measured from xylan substrate. These results are of interest for lignocellulose biomass valorization and demonstrated the potential of termites and their symbiotic microbiota as a source of interesting enzymes for oligosaccharides production. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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2340 KiB

Open AccessArticle

Atomic Model and Micelle Dynamics of QS-21 Saponin

by Conrado Pedebos, Laércio Pol-Fachin, Ramon Pons, Cilâine V. Teixeira and Hugo Verli

Molecules 2014, 19(3), 3744-3760; https://doi.org/10.3390/molecules19033744 - 24 Mar 2014

Cited by 22 | Viewed by 9536

Abstract

QS-21 is a saponin extracted from Quillaja saponaria, widely investigated as a vaccine immunoadjuvant. However, QS-21 use is mainly limited by its chemical instability, significant variety in molecular composition and low tolerance dose in mammals. Also, this compound tends to form micelles in a concentration-dependent manner. Here, we aimed to characterize its conformation and the process of micelle formation, both experimentally and computationally. Therefore, molecular dynamics (MD) simulations were performed in systems containing different numbers of QS-21 molecules in aqueous solution, in order to evaluate the spontaneous micelle formation. The applied methodology allowed the generation of micelles whose sizes were shown to be in high agreement with small-angle X-ray scattering (SAXS). Furthermore, the ester linkage between fucose and acyl chain was less solvated in the micellar form, suggesting a reduction in hydrolysis. This is the first atomistic interpretation of previous experimental data, the first micellar characterization of saponin micelles by SAXS and first tridimensional model of a micelle constituted of saponins, contributing to the understanding of the molecular basis of these compounds. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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2126 KiB

Open AccessArticle

EGF Receptor-Dependent Mechanism May be Involved in the Tamm–Horsfall Glycoprotein-Enhanced PMN Phagocytosis via Activating Rho Family and MAPK Signaling Pathway

by Ko-Jen Li, Sue-Cien Siao, Cheng-Han Wu, Chieh-Yu Shen, Tsai-Hung Wu, Chang-Youh Tsai, Song-Chou Hsieh and Chia-Li Yu

Molecules 2014, 19(1), 1328-1343; https://doi.org/10.3390/molecules19011328 - 21 Jan 2014

Cited by 10 | Viewed by 7083

Abstract

Our previous studies showed that urinary Tamm–Horsfall glycoprotein (THP) potently enhanced polymorphonuclear neutrophil (PMN) phagocytosis. However, the domain structure(s), signaling pathway and the intracellular events responsible for THP-enhanced PMN phagocytosis remain to be elucidated. THP was purified from normal human urine. The human promyelocytic leukemia cell line HL-60 was induced to differentiate into PMNs by all-trans retinoid acid. Pretreatment with different MAPK and PI3K inhibitors was used to delineate signaling pathways in THP-enhanced PMN phagocytosis. Phosphorylation of molecules responsible for PMN phagocytosis induced by bacterial lipopolysaccharide (LPS), THP, or human recombinant epidermal growth factor (EGF) was evaluated by western blot. A p38 MAPK inhibitor, SB203580, effectively inhibited both spontaneous and LPS- and THP-induced PMN phagocytosis. Both THP and LPS enhanced the expression of the Rho family proteins Cdc42 and Rac that may lead to F-actin re-arrangement. Further studies suggested that THP and EGF enhance PMN and differentiated HL-60 cell phagocytosis in a similar pattern. Furthermore, the EGF receptor inhibitor GW2974 significantly suppressed THP- and EGF-enhanced PMN phagocytosis and p38 and ERK1/2 phosphorylation in differentiated HL-60 cells. We conclude that EGF receptor-dependent signaling may be involved in THP-enhanced PMN phagocytosis by activating Rho family and MAP kinase. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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402 KiB

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A New Chemical Approach to Human ABO Histo-Blood Group Type 2 Antigens

by Atsushi Hara, Akihiro Imamura, Hiromune Ando, Hideharu Ishida and Makoto Kiso

Molecules 2014, 19(1), 414-437; https://doi.org/10.3390/molecules19010414 - 31 Dec 2013

Cited by 25 | Viewed by 12500

Abstract

A new chemical approach to synthesizing human ABO histo-blood type 2 antigenic determinants was developed. N-Phthaloyl-protected lactosaminyl thioglycoside derived from lactulose via the Heyns rearrangement was employed to obtain a type 2 core disaccharide. Use of this scheme lowered the overall number of reaction steps. Stereoselective construction of the α-galactosaminide/galactoside found in A- and B-antigens, respectively, was achieved by using a unique di-tert-butylsilylene-directed α-glycosylation method. The proposed synthetic scheme provides an alternative to existing procedures for preparing ABO blood group antigens. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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