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.

Single glycan-protein interactions are often weak, such that glycan binding partnerscommonly utilizemultiple, spatially defined binding sites to enhance binding avidity and specificity.C urrent array technologiesu sually neglect defined multivalent display.L aser-based array synthesis technology allows for flexible and rapid on-surface synthesis of different peptides. By combining this technique with click chemistry,n eo-glycopeptides werep roduced directly on a functionalized glass slide in the microarray format. Density and spatial distribution of carbohydrates can be tuned, resulting in well-defined glycan structures for multivalent display.T he two lectins concanavalin Aa nd langerin were probedw ith different glycanso nm ultivalent scaffolds, revealing strong spacing-, density-, and ligand-dependent binding. In addition, we could also measuret he surfaced issociation constant.T his approach allows for ar apid generation, screening, and optimization of am ultitudeo fm ultivalent scaffoldsfor glycan binding.

In this introductory lecture we discuss the state-of-the-art glycan microarray technology, with emphasis on novel approaches to immobilize collections of glycans in a defined, multivalent manner.

A low‐cost laser‐based printing setup is presented, which allows for the spot‐wise patterning of surfaces with defined polymer nanolayers. These nanolayer spots serve as a “solid solvent,” embedding different chemicals, chemical building blocks, materials, or precursors and can be stacked on top of each other. By melting the spot pattern, the polymer‐embedded molecules are released for chemical reaction. This enables researchers to quickly pattern a surface with different molecules and materials, mixing them directly on the surface for high‐throughput chemical synthesis to generate and screen diverse microarray libraries. In contrast to expensive ink‐jet or contact printing, this approach does not require premixing of inks, which enables in situ combinatorial mixing. Easy access and versatility of this patterning approach are shown by generating microarrays of various biomolecules, such as glycans for the first time, to screen interactions of antibodies and lectins. In addition, a layer‐by‐layer solid‐phase synthesis of peptides directly on the microarray is presented. Amino acid–containing nanolayers are repeatedly laser‐transferred and reacted with the functionalized acceptor surface in defined patterns. This simple system enables a reproducible array production, down to spot‐to‐spot distances of 100 µm, and offers a flexible and cheap alternative to expensive spotting robot technology.

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Hereinw er eport ac hemical synthesis towards new modified hyaluronic acid oligomers by using only commercially available d-glucose and d-glucosamineh ydrochloride. The variousp rotected hyaluronic acid disaccharides were synthesized bearing new functional groups at C-6 of the b-d-glucuronic acid moiety with av iew to structure-related biological activityt ests. The orthogonal protecting group pattern allows ready access to the corresponding higher oligomers. Also, 1 HNMR studies of the new derivatives demonstrated the effect of the variousf unctional groups on the intramolecularelectronic environment.

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.

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