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Synthesis and Biological Applications of Glycoconjugates

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

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 50650

Special Issue Editor


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Guest Editor
Laboratory for Biomaterials, Institute of Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany
Interests: glycoconjugates; enzyme cascade reactions; chemo-enzymatic synthesis; glycosyltransferases; nucleotide sugars; galectins; lectins; glycopolymers; biosensors; biomaterials
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Special Issue Information

Dear Colleagues,

Glycans are parts of glycoconjugates (glycoproteins, glycolipids, proteoglycans) and are involved in numerous biological recognition events. Glycans are considered as encoding molecules. Maintaining, for example, cellular crosstalk on a molecular level is directly related to the vast chemical diversity of glycan structures. Glycan assembly by chemical and/or enzymatic synthesis is therefore challenging. Novel and efficient synthetic procedures for glycan-based products need to be developed and optimized. Especially, multi-enzyme cascade reactions are of great interest for the production of glycans in larger scale. Protein engineering of enzymes leads to tailored biocatalysts with favorable and novel properties. Most importantly, the combination of chemo- and biocatalysis will expand the scope of novel routes for the synthesis of glycoconjugates. In this way, complex glycans and neo-glycoconjugates will be accessible for their application.

Decoding of glycan information by carbohydrate recognizing molecules (lectins, antibodies, aptamers) is closely related to their multivalent glycan presentation on surface scaffolds, the glyco-biointerface. Monitoring the read-out of binding events can then efficiently be translated in diagnostic and therapeutic biomedical applications.

With this little overview, I cordially invite you to contribute and share your recent research results in this Special Issue on the synthesis and biological applications of glycoconjugates.

Prof. Dr. Lothar Elling
Guest Editor

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Keywords

  • glycoproteins
  • glycolipids
  • proteoglycans
  • biocatalysis
  • cascade reactions
  • chemo-enzymatic synthesis
  • lectins
  • biomaterials
  • glycopolymers
  • biosensors

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Published Papers (7 papers)

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Research

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2705 KiB  
Article
Preparation and Bioactivity Assessment of Chitosan-1-Acetic Acid-5-Flurouracil Conjugates as Cancer Prodrugs
by Mohsin O. Mohammed, Kameran S. Hussain and Nadia Q. Haj
Molecules 2017, 22(11), 1629; https://doi.org/10.3390/molecules22111629 - 08 Nov 2017
Cited by 15 | Viewed by 6262
Abstract
5-fluorouracil (5-FU) is a specific anti-cancer agent that is generally used to treat gastrointestinal, colorectal, and breast cancer. In this work, chitosan (CS) was extracted from local fish scales using an established method. 5-FU was then converted to 1-acetic acid-5-fluorouracil (FUAC) and reacted [...] Read more.
5-fluorouracil (5-FU) is a specific anti-cancer agent that is generally used to treat gastrointestinal, colorectal, and breast cancer. In this work, chitosan (CS) was extracted from local fish scales using an established method. 5-FU was then converted to 1-acetic acid-5-fluorouracil (FUAC) and reacted with this CS to prepare chitosan-1-acetic acid-5-fluorouracil (CS-FUAC) conjugates as a colon-specific prodrug. All compounds were characterized by Proton nuclear magnetic resonance (1H-NMR), Fourier-transform infrared (FTIR), and UV-visible spectroscopy. The synthesized compound was subjected to a chemical stability study in phosphate buffer (0.2 M, pH 7.4) and in KCl/HCl buffer (0.2 M, pH 1.2) at different time intervals (0–240 min) and incubation at 37 °C. This revealed a significantly greater stability and a longer half-life for the CS-FUAC than for FUAC. Hemolytic activity results indicated a much lower toxicity for CS-FUAC than for 5-FU and supported consideration of CS-FUAC for further biological screening and application trials. The percentage of FUAC in the conjugates was determined by subjecting the prodrug to treatment in basic media to hydrolyze the amide bond, followed by absorbency measurements at 273 nm. The cytotoxicity studies of the conjugates were also evaluated on human colorectal cancer cell line (HT-29), which showed that the conjugates are more cytotoxic than the free drug. Therefore, CS-FUAC conjugates can be considered to represent potential colon-specific drug delivery agents, with minimal undesirable side effects, for colon cancer therapy. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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2327 KiB  
Article
Enzymatic Synthesis of N-Acetyllactosamine (LacNAc) Type 1 Oligomers and Characterization as Multivalent Galectin Ligands
by Thomas Fischöder, Dominic Laaf, Carina Dey and Lothar Elling
Molecules 2017, 22(8), 1320; https://doi.org/10.3390/molecules22081320 - 10 Aug 2017
Cited by 32 | Viewed by 9896
Abstract
Repeats of the disaccharide unit N-acetyllactosamine (LacNAc) occur as type 1 (Galβ1, 3GlcNAc) and type 2 (Galβ1, 4GlcNAc) glycosylation motifs on glycoproteins and glycolipids. The LacNAc motif acts as binding ligand for lectins and is involved in many biological recognition events. To [...] Read more.
Repeats of the disaccharide unit N-acetyllactosamine (LacNAc) occur as type 1 (Galβ1, 3GlcNAc) and type 2 (Galβ1, 4GlcNAc) glycosylation motifs on glycoproteins and glycolipids. The LacNAc motif acts as binding ligand for lectins and is involved in many biological recognition events. To the best of our knowledge, we present, for the first time, the synthesis of LacNAc type 1 oligomers using recombinant β1,3-galactosyltransferase from Escherichia coli and β1,3-N-acetylglucosaminyltranferase from Helicobacter pylori. Tetrasaccharide glycans presenting LacNAc type 1 repeats or LacNAc type 1 at the reducing or non-reducing end, respectively, were conjugated to bovine serum albumin as a protein scaffold by squarate linker chemistry. The resulting multivalent LacNAc type 1 presenting neo-glycoproteins were further studied for specific binding of the tumor-associated human galectin 3 (Gal-3) and its truncated counterpart Gal-3∆ in an enzyme-linked lectin assay (ELLA). We observed a significantly increased affinity of Gal-3∆ towards the multivalent neo-glycoprotein presenting LacNAc type 1 repeating units. This is the first evidence for differences in glycan selectivity of Gal-3∆ and Gal-3 and may be further utilized for tracing Gal-3∆ during tumor progression and therapy. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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1944 KiB  
Article
The Influence of Glycosylation of Natural and Synthetic Prenylated Flavonoids on Binding to Human Serum Albumin and Inhibition of Cyclooxygenases COX-1 and COX-2
by Tomasz Tronina, Paulina Strugała, Jarosław Popłoński, Aleksandra Włoch, Sandra Sordon, Agnieszka Bartmańska and Ewa Huszcza
Molecules 2017, 22(7), 1230; https://doi.org/10.3390/molecules22071230 - 21 Jul 2017
Cited by 36 | Viewed by 6460
Abstract
The synthesis of different classes of prenylated aglycones (α,β-dihydroxanthohumol (2) and (Z)-6,4’-dihydroxy-4-methoxy-7-prenylaurone (3)) was performed in one step reactions from xanthohumol (1)—major prenylated chalcone naturally occurring in hops. Obtained flavonoids (23) [...] Read more.
The synthesis of different classes of prenylated aglycones (α,β-dihydroxanthohumol (2) and (Z)-6,4’-dihydroxy-4-methoxy-7-prenylaurone (3)) was performed in one step reactions from xanthohumol (1)—major prenylated chalcone naturally occurring in hops. Obtained flavonoids (23) and xanthohumol (1) were used as substrates for regioselective fungal glycosylation catalyzed by two Absidia species and Beauveria bassiana. As a result six glycosides (49) were formed, of which four glycosides (69) have not been published so far. The influence of flavonoid skeleton and the presence of glucopyranose and 4-O-methylglucopyranose moiety in flavonoid molecule on binding to main protein in plasma, human serum albumin (HSA), and inhibition of cyclooxygenases COX-1 and COX-2 were investigated. Results showed that chalcone (1) had the highest binding affinity to HSA (8.624 × 104 M−1) of all tested compounds. It has also exhibited the highest inhibition of cyclooxygenases activity, and it was a two-fold stronger inhibitor than α,β-dihydrochalcone (2) and aurone (3). The presence of sugar moiety in flavonoid molecule caused the loss of HSA binding activity as well as the decrease in inhibition of cyclooxygenases activity. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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2248 KiB  
Article
Glycosylation of Recombinant Antigenic Proteins from Mycobacterium tuberculosis: In Silico Prediction of Protein Epitopes and Ex Vivo Biological Evaluation of New Semi-Synthetic Glycoconjugates
by Teodora Bavaro, Sara Tengattini, Luciano Piubelli, Francesca Mangione, Roberta Bernardini, Vincenzina Monzillo, Sandra Calarota, Piero Marone, Massimo Amicosante, Loredano Pollegioni, Caterina Temporini and Marco Terreni
Molecules 2017, 22(7), 1081; https://doi.org/10.3390/molecules22071081 - 29 Jun 2017
Cited by 17 | Viewed by 5752
Abstract
Tuberculosis is still one of the most deadly infectious diseases worldwide, and the use of conjugated antigens, obtained by combining antigenic oligosaccharides, such as the lipoarabinomannane (LAM), with antigenic proteins from Mycobacterium tuberculosis (MTB), has been proposed as a new strategy for developing [...] Read more.
Tuberculosis is still one of the most deadly infectious diseases worldwide, and the use of conjugated antigens, obtained by combining antigenic oligosaccharides, such as the lipoarabinomannane (LAM), with antigenic proteins from Mycobacterium tuberculosis (MTB), has been proposed as a new strategy for developing efficient vaccines. In this work, we investigated the effect of the chemical glycosylation on two recombinant MTB proteins produced in E. coli with an additional seven-amino acid tag (recombinant Ag85B and TB10.4). Different semi-synthetic glycoconjugated derivatives were prepared, starting from mannose and two disaccharide analogs. The glycans were activated at the anomeric position with a thiocyanomethyl group, as required for protein glycosylation by selective reaction with lysines. The glycosylation sites and the ex vivo evaluation of the immunogenic activity of the different neo-glycoproteins were investigated. Glycosylation does not modify the immunological activity of the TB10.4 protein. Similarly, Ag85B maintains its B-cell activity after glycosylation while showing a significant reduction in the T-cell response. The results were correlated with the putative B- and T-cell epitopes, predicted using a combination of in silico systems. In the recombinant TB10.4, the unique lysine is not included in any T-cell epitope. Lys30 of Ag85B, identified as the main glycosylation site, proved to be the most important site involved in the formation of T-cell epitopes, reasonably explaining why its glycosylation strongly influenced the T-cell activity. Furthermore, additional lysines included in different epitopes (Lys103, -123 and -282) are also glycosylated. In contrast, B-cell epitopic lysines of Ag85B were found to be poorly glycosylated and, thus, the antibody interaction of Ag85B was only marginally affected after coupling with mono- or disaccharides. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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5223 KiB  
Article
Roles of Glycoproteins in the Diagnosis and Differential Diagnosis of Chronic and Latent Keshan Disease
by Sen Wang, Zheng Fan, Bing Zhou, Yingting Wang, Peiru Du, Wuhong Tan, Mikko J. Lammi and Xiong Guo
Molecules 2017, 22(5), 746; https://doi.org/10.3390/molecules22050746 - 08 May 2017
Cited by 8 | Viewed by 4654
Abstract
We aimed to explore the roles of glycoproteins in the pathogenesis of chronic and latent Keshan disease (CKD and LKD), and screen the lectins as indicators of significant differences in glycoproteins of KD saliva and serum. Blood and saliva were collected from 50 [...] Read more.
We aimed to explore the roles of glycoproteins in the pathogenesis of chronic and latent Keshan disease (CKD and LKD), and screen the lectins as indicators of significant differences in glycoproteins of KD saliva and serum. Blood and saliva were collected from 50 CKD, 50 LKD patients and 54 normal individuals. Saliva and serum lectin microarrays and saliva and serum microarrays were used to screen and verify the differences in the levels of lectin among the three groups. In the male saliva lectin microarray, Solanum tuberosum (potato) lectin (STL) and other 9 lectins showed differences between CKD and normal; STL and other 9 lectins showed differences between LKD and normal; Aleuria aurantia lectin (AAL) and other 15 lectins showed differences between CKD and LKD. In the female saliva microarray, Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) and other 9 lectins showed differences between CKD and normal; STL and other 7 lectins showed differences between LKD and normal; Maackia amurensis lectin I (MAL-I) and Triticum vulgaris (WGA) showed difference between CKD and LKD. In the male serum lectin microarray, Psophocarpus tetragonolobus lectin I (PTL-I) and other 16 lectins showed differences between CKD and normal; Ulexeuropaeus agglutinin I (UEA-I) and other 9 lectins showed differences between LKD and normal; AAL and other 13 lectins showed differences between CKD and LKD. In the female serum lectin microarray, WGA and other 13 lectins showed differences between CKD and normal; Euonymus europaeus lectin (EEL) and other 6 lectins showed differences between LKD and normal; MAL-I and other 14 lectins showed differences between CKD and LKD. Carbohydrate chain GlcNAc and α-Gal may play crucial roles in the pathogenesis of KD. STL may be considered the diagnostic biomarker for male CKD and LKD, while WGA may be useful in distinguishing between the two stages. STL may be considered the diagnostic biomarker for female LKD. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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3843 KiB  
Article
Evaluation of Maltose-Based Cationic Liposomes with Different Hydrophobic Tails for Plasmid DNA Delivery
by Bo Li, Liangliang Deng, Meiyan Liu and Youlin Zeng
Molecules 2017, 22(3), 406; https://doi.org/10.3390/molecules22030406 - 12 Mar 2017
Cited by 3 | Viewed by 5502
Abstract
In this paper, three cationic glycolipids with different hydrophobic chains Malt-DiC12MA (IX a), Malt-DiC14MA (IX b) and Malt-DiC16MA (IX c) were constructed by using maltose as starting material via peracetylation, selective 1-O-deacetylation, trichloroacetimidation, glycosylation, azidation, [...] Read more.
In this paper, three cationic glycolipids with different hydrophobic chains Malt-DiC12MA (IX a), Malt-DiC14MA (IX b) and Malt-DiC16MA (IX c) were constructed by using maltose as starting material via peracetylation, selective 1-O-deacetylation, trichloroacetimidation, glycosylation, azidation, deacetylation, Staudinger reaction, tertiary amination and quaternization. Target compounds and some intermediates were characterized by 1H-NMR, 13C-NMR, 1H-1H COSY and 1H-13C HSQC. The results of gel electrophoresis assay, atomic force microscopy images (AFM) and dynamic light scattering (DLS) demonstrate that all the liposomes could efficiently bind and compact DNA (N/P ratio less than 2) into nanoparticles with proper size (88 nm–146 nm, PDI < 0.4) and zeta potential (+15 mV–+26 mV). The transfection efficiency and cellular uptake of glycolipids in HEK293 cell were evaluated through the enhanced green fluorescent protein (EGFP) expression and Cy3-labeled pEGFP-C1 (Enhanced Green Fluorescent Protein plasmid) images, respectively. Importantly, it indicated that Malt-DiC14MA exhibited high gene transfer efficiency and better uptake capability at N/P ratios of 8:1. Additionally, the result of cell viability showed glycolipids exhibited low biotoxicity and good biocompatibility by thiazolyl blue tetrazolium bromide (MTT) assay. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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Review

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7861 KiB  
Review
Synthesis of Glycosides by Glycosynthases
by Marc R. Hayes and Jörg Pietruszka
Molecules 2017, 22(9), 1434; https://doi.org/10.3390/molecules22091434 - 30 Aug 2017
Cited by 62 | Viewed by 11327
Abstract
The many advances in glycoscience have more and more brought to light the crucial role of glycosides and glycoconjugates in biological processes. Their major influence on the functionality and stability of peptides, cell recognition, health and immunity and many other processes throughout biology [...] Read more.
The many advances in glycoscience have more and more brought to light the crucial role of glycosides and glycoconjugates in biological processes. Their major influence on the functionality and stability of peptides, cell recognition, health and immunity and many other processes throughout biology has increased the demand for simple synthetic methods allowing the defined syntheses of target glycosides. Additional interest in glycoside synthesis has arisen with the prospect of producing sustainable materials from these abundant polymers. Enzymatic synthesis has proven itself to be a promising alternative to the laborious chemical synthesis of glycosides by avoiding the necessity of numerous protecting group strategies. Among the biocatalytic strategies, glycosynthases, genetically engineered glycosidases void of hydrolytic activity, have gained much interest in recent years, enabling not only the selective synthesis of small glycosides and glycoconjugates, but also the production of highly functionalized polysaccharides. This review provides a detailed overview over the glycosylation possibilities of the variety of glycosynthases produced until now, focusing on the transfer of the most common glucosyl-, galactosyl-, xylosyl-, mannosyl-, fucosyl-residues and of whole glycan blocks by the different glycosynthase enzyme variants. Full article
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)
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