The extracellular matrix (ECM) constitutes a highly dynamic three-dimensional structural network comprised of macromolecules, such as proteoglycans/glycosaminoglycans (PGs/GAGs), collagens, laminins, fibronectin, elastin, other glycoproteins and proteinases In recent years, the field of PGs has expanded rapidly Due to their high structural complexity and heterogeneity, PGs mediate several homeostatic and pathological processes PGs consist of a protein core and one or more covalently attached GAG chains, which provide the protein cores with the ability to interact with several proteins The GAG building blocks of PGs significantly influence the chemical and functional properties of PGs The primary goal of this comprehensive review is to summarize major achievements and paradigm-shifting discoveries made on the PG/GAG chemistry-biology axis, focusing on structural variability, structure-function relationships, metabolic, molecular, and epigenetic mechanisms underlying their synthesis Recent insights related to exosome biogenesis, degradation, and cell signaling, their status as diagnostic tools and potential pharmacological targets in diseases as well as current applications in nanotechnology and biotechnology are addressed Moreover, issues related to docking studies, molecular modeling, GAG/PG interaction networks, and their integration are discussed

Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics.

https://repositorio-aberto.up.pt/bitstream/10216/111839/1/j.cellimm.2018.03.007.pdf

Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis.

Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation. Commentary

The translation of biological glycosylation in humans to the clinical applications involves systematic studies using homogeneous samples of oligosaccharides and glycoconjugates, which could be accessed by chemical, enzymatic or other biological methods. However, the structural complexity and wide-range variations of glycans and their conjugates represent a major challenge in the synthesis of this class of biomolecules. To help navigate within many methods of oligosaccharide synthesis, this Perspective offers a critical assessment of the most promising synthetic strategies with an eye on the therapeutically relevant targets.

Oligosaccharide Synthesis and Translational Innovation

Heparan sulfates (HS) are linear sulfated polysaccharides that modulate a wide range of physiological and disease-processes. Variations in HS epimerization and sulfation provide enormous structural diversity, which is believed to underpin protein binding and regulatory properties. The ligand requirements of HS-binding proteins have, however, been defined in only a few cases. We describe here a synthetic methodology that can rapidly provide a library of well-defined HS oligosaccharides. It is based on the use of modular disaccharides to assemble several selectively protected tetrasaccharides that were subjected to selective chemical modifications such as regioselective O- and N-sulfation and selective de-sulfation. A number of the resulting compounds were subjected to enzymatic modifications by 3-O-sulfotransferases-1 (3-OST1) to provide 3-O-sulfated derivatives. The various approaches for diversification allowed one tetrasaccharide to be converted into 12 differently sulfated derivatives. By employing tetrasaccharides with different backbone compositions, a library of 47 HS-oligosaccharides was prepared and the resulting compounds were used to construct a HS microarray. The ligand requirements of a number of HS-binding proteins including fibroblast growth factor 2 (FGF-2), and the chemokines CCL2, CCL5, CCL7, CCL13, CXCL8, and CXCL10 were examined using the array. Although all proteins recognized multiple compounds, they exhibited clear differences in structure-binding characteristics. The HS microarray data guided the selection of compounds that could interfere in biological processes such as cell proliferation. Although the library does not cover the entire chemical space of HS-tetrasaccharides, the binding data support a notion that changes in cell surface HS composition can modulate protein function.

/pdf/heparan-sulfate-microarray-reveals-that-heparan-sulfate-3hf7h9osgp.pdf

Heparan Sulfate Microarray Reveals That Heparan Sulfate–Protein Binding Exhibits Different Ligand Requirements

Glycosaminoglycans (GAGs) as one major part of the glycocalyx are involved in many essential biological cell processes, as well as in many courses of diseases. Because of the potential therapeutic application of GAG polymers, fragments, and also derivatives toward different diseases (e.g., heparin derivatives against Alzheimer’s disease), there is a continual growing demand for new chemical syntheses, which suffice the high claim to stereoselectivity and chemoselectivity. This Review summarizes the progress of chemical syntheses of GAGs over the last 10 years. For each class of the glycosaminoglycans—hyaluronan (HA), heparan sulfate/heparin (HS/HP), chondroitin/dermatan sulfate (CS/DS), and keratan sulfate (KS)—mainly novel glycosylation strategies, elongation sequences, and protecting group patterns are discussed, but also (semi)automated syntheses, enzymatic approaches, and functionalizations of synthesized or isolated GAGs are considered.

Chemical Synthesis of Glycosaminoglycans.

Herein we report a chemical synthesis towards new modified hyaluronic acid oligomers by using only commercially available d-glucose and d-glucosamine hydrochloride. The various protected hyaluronic acid disaccharides were synthesized bearing new functional groups at C-6 of the β-d-glucuronic acid moiety with a view to structure-related biological activity tests. The orthogonal protecting group pattern allows ready access to the corresponding higher oligomers. Also, 1H NMR studies of the new derivatives demonstrated the effect of the various functional groups on the intramolecular electronic environment.

https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/chem.201701238

Chemical Synthesis of Modified Hyaluronic Acid Disaccharides

The article contains sections titled: 

1.	Introduction	
2.	Physical Properties of Sodium Azide	
3.	Chemical Properties of Sodium Azide and Hydrazoic Acid	
4.	Production	
4.1.	Sodium Azide	
4.2.	Hydrazoic Acid	
5.	Quality Specifications and Analysis	
6.	Storage and Transportation	
7.	Application of Sodium Azide	
8.	Other Derivatives and Salts	
8.1.	Metal Salts	
8.2.	Organic Azides in Fine Chemical Synthesis	
8.3.	Organic Reactions of Azides	
9.	Safety Precautions and Environmental Protection	
10.	Economic Aspects	
11.	Toxicology and Occupational Health

Hydrazoic Acid and Azides

Laser‐induced forward transfer (LIFT) is a rapid laser‐patterning technique for high‐throughput combinatorial synthesis directly on glass slides. A lack of automation and precision limits LIFT applications to simple proof‐of‐concept syntheses of fewer than 100 compounds. Here, an automated synthesis instrument is reported that combines laser transfer and robotics for parallel synthesis in a microarray format with up to 10 000 individual reactions cm−2. An optimized pipeline for amide bond formation is the basis for preparing complex peptide microarrays with thousands of different sequences in high yield with high reproducibility. The resulting peptide arrays are of higher quality than commercial peptide arrays. More than 4800 15‐residue peptides resembling the entire Ebola virus proteome on a microarray are synthesized to study the antibody response of an Ebola virus infection survivor. Known and unknown epitopes that serve now as a basis for Ebola diagnostic development are identified. The versatility and precision of the synthesizer is demonstrated by in situ synthesis of fluorescent molecules via Schiff base reaction and multi‐step patterning of precisely definable amounts of fluorophores. This automated laser transfer synthesis approach opens new avenues for high‐throughput chemical synthesis and biological screening.

/pdf/automated-laser-transfer-synthesis-of-high-density-2i0h4vbg.pdf

Automated Laser‐Transfer Synthesis of High‐Density Microarrays for Infectious Disease Screening

Automated chemical synthesis has revolutionized synthetic access to biopolymers in terms of simplicity and speed. While automated oligosaccharide synthesis has become faster and more versatile, the parallel synthesis of oligosaccharides is not yet possible. Here, a chemical vapor glycosylation strategy (VaporSPOT) is described that enables the simultaneous synthesis of oligosaccharides on a cellulose membrane solid support. Different linkers allow for flexible and straightforward cleavage, purification, and characterization of the target oligosaccharides. This method is the basis for the development of parallel automated glycan synthesis platforms.

/pdf/vaporspot-parallel-synthesis-of-oligosaccharides-on-12cqbo3s.pdf

Marco Mende

Papers

Chemical Synthesis of Glycosaminoglycans.

Chemical Synthesis of Modified Hyaluronic Acid Disaccharides

Hydrazoic Acid and Azides

Automated Laser‐Transfer Synthesis of High‐Density Microarrays for Infectious Disease Screening

VaporSPOT: Parallel Synthesis of Oligosaccharides on Membranes