Publications by authors named "Peter H Seeberger"

420 Publications

Chimeric oligosaccharide conjugate induces opsonic antibodies against serotypes 19A and 19F.

Chem Sci 2020 Jun 26;11(28):7401-7407. Epub 2020 Jun 26.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces Am Mūhlenberg 1 D-14424 Potsdam Germany

19A (ST19A) and 19F (ST19F) are among the prevalent serotypes causing pneumococcal disease worldwide even after introduction of a 13-valent pneumococcal conjugate vaccine (PCV13). Synthetic glycoconjugate vaccines have defined chemical structures rather than isolated polysaccharide mixtures utilized in marketed vaccines. Ideally, a minimal number of synthetic antigens would cover as many bacterial serotypes to lower cost of goods and minimize the response to carrier proteins. To demonstrate that a chimeric oligosaccharide antigen can induce a protective immune response against multiple serotypes, we synthesized a chimeric antigen (ST19AF) that is comprised of a repeating unit of ST19A and ST19F capsular polysaccharide each. Synthetic glycan epitopes representing only ST19A, and ST19F were prepared for comparison. Semisynthetic glycoconjugates containing chimeric antigen ST19AF induced high antibody titers able to recognize native CPS from ST19A and ST19F in rabbits. The antibodies were able to kill both strains of . Chimeric antigens are an attractive means to induce an immune response against multiple bacterial serotypes.
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http://dx.doi.org/10.1039/d0sc02230fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159444PMC
June 2020

Automated Assembly of Starch and Glycogen Polysaccharides.

J Am Chem Soc 2021 Jun 11. Epub 2021 Jun 11.

Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

Polysaccharides are Nature's most abundant biomaterials essential for plant cell wall construction and energy storage. Seemingly minor structural differences result in entirely different functions: cellulose, a β (1-4) linked glucose polymer, forms fibrils that can support large trees, while amylose, an α (1-4) linked glucose polymer forms soft hollow fibers used for energy storage. A detailed understanding of polysaccharide structures requires pure materials that cannot be isolated from natural sources. Automated Glycan Assembly provides quick access to -linked glycans analogues of cellulose, but the stereoselective installation of multiple -glycosidic linkages present in amylose has not been possible to date. Here, we identify thioglycoside building blocks with different protecting group patterns that, in concert with temperature and solvent control, achieve excellent stereoselectivity during the synthesis of linear and branched α-glucan polymers with up to 20 -glycosidic linkages. The molecules prepared with the new method will serve as probes to understand the biosynthesis and the structure of α-glucans.
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http://dx.doi.org/10.1021/jacs.1c02188DOI Listing
June 2021

Identifying the origin of local flexibility in a carbohydrate polymer.

Proc Natl Acad Sci U S A 2021 Jun;118(23)

Nanoscale Science Department, Max Planck Institute for Solid State Research, 70569 Stuttgart, Germany;

Correlating the structures and properties of a polymer to its monomer sequence is key to understanding how its higher hierarchy structures are formed and how its macroscopic material properties emerge. Carbohydrate polymers, such as cellulose and chitin, are the most abundant materials found in nature whose structures and properties have been characterized only at the submicrometer level. Here, by imaging single-cellulose chains at the nanoscale, we determine the structure and local flexibility of cellulose as a function of its sequence (primary structure) and conformation (secondary structure). Changing the primary structure by chemical substitutions and geometrical variations in the secondary structure allow the chain flexibility to be engineered at the single-linkage level. Tuning local flexibility opens opportunities for the bottom-up design of carbohydrate materials.
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http://dx.doi.org/10.1073/pnas.2102168118DOI Listing
June 2021

Microwave-Assisted Automated Glycan Assembly.

J Am Chem Soc 2021 Jun 1;143(23):8893-8901. Epub 2021 Jun 1.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, 14476 Potsdam, Germany.

Automated synthesis of DNA, RNA, and peptides provides quickly and reliably important tools for biomedical research. Automated glycan assembly (AGA) is significantly more challenging, as highly branched carbohydrates require strict regio- and stereocontrol during synthesis. A new AGA synthesizer enables rapid temperature adjustment from -40 to +100 °C to control glycosylations at low temperature and accelerates capping, protecting group removal, and glycan modifications using elevated temperatures. Thereby, the temporary protecting group portfolio is extended from two to four orthogonal groups that give rise to oligosaccharides with up to four branches. In addition, sulfated glycans and unprotected glycans can be prepared. The new design reduces the typical coupling cycles from 100 to 60 min while expanding the range of accessible glycans. The instrument drastically shortens and generalizes the synthesis of carbohydrates for use in biomedical and material science.
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http://dx.doi.org/10.1021/jacs.1c03851DOI Listing
June 2021

Laser-driven growth of structurally defined transition metal oxide nanocrystals on carbon nitride photoelectrodes in milliseconds.

Nat Commun 2021 May 28;12(1):3224. Epub 2021 May 28.

Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.

Fabrication of hybrid photoelectrodes on a subsecond timescale with low energy consumption and possessing high photocurrent densities remains a centerpiece for successful implementation of photoelectrocatalytic synthesis of fuels and value-added chemicals. Here, we introduce a laser-driven technology to print sensitizers with desired morphologies and layer thickness onto different substrates, such as glass, carbon, or carbon nitride (CN). The specially designed process uses a thin polymer reactor impregnated with transition metal salts, confining the growth of transition metal oxide (TMO) nanostructures on the interface in milliseconds, while their morphology can be tuned by the laser. Multiple nano-p-n junctions at the interface increase the electron/hole lifetime by efficient charge trapping. A hybrid copper oxide/CN photoanode with optimal architecture reaches 10 times higher photocurrents than the pristine CN photoanode. This technology provides a modular approach to build a library of TMO-based composite films, enabling the creation of materials for diverse applications.
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http://dx.doi.org/10.1038/s41467-021-23367-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163840PMC
May 2021

Non-Covalent Microarrays from Synthetic Amino-Terminating Glycans-Implications in Expanding Glycan Microarray Diversity and Platform Comparison.

Glycobiology 2021 May 8. Epub 2021 May 8.

Glycosciences Laboratory, Imperial College London, London W12 0NN, United Kingdom.

Glycan microarrays have played important roles in detection and specificity assignment of glycan-recognition by proteins. However, the size and diversity of glycan libraries in current microarray systems are small compared to estimated glycomes, and these may lead to missed detection or incomplete assignment. For microarray construction, covalent and non-covalent immobilization are the two types of methods used, but a direct comparison of results from the two platforms is required. Here we develop a chemical strategy to prepare lipid-linked probes from both naturally-derived aldehyde-terminating and synthetic amino-terminating glycans that addresses the two aspects: expansion of sequence-defined glycan libraries and comparison of the two platforms. We demonstrate the specific recognition by plant and mammalian lectins, carbohydrate-binding modules and antibodies, and the overall similarities from the two platforms. Our results provide new knowledge on unique glycan-binding specificities for the immune-receptor Dectin-1 towards β-glucans and the interaction of rotavirus P[19] adhesive protein with mucin O-glycan cores.
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http://dx.doi.org/10.1093/glycob/cwab037DOI Listing
May 2021

Automated Glycan Assembly of Oligogalactofuranosides Reveals the Influence of Protecting Groups on Oligosaccharide Stability.

J Org Chem 2021 May 7;86(10):7280-7287. Epub 2021 May 7.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, 14476 Potsdam, Germany.

Galactofurans are an important structural constituent of arabinogalactan and lipopolysaccharides (LPS) ubiquitously present on the envelopes of all . Key to the automated glycan assembly (AGA) of linear galactofuranosides as long as 20-mers was the identification of thioglycoside building blocks with a fine balance of stereoelectronic and steric effects to ensure the stability of oligogalactofuranoside during the synthesis. A benzoylated galactofuranose thioglycoside building block proved most efficient for oligosaccharide construction.
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http://dx.doi.org/10.1021/acs.joc.1c00505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154612PMC
May 2021

Longitudinal Development of Antibody Responses in COVID-19 Patients of Different Severity with ELISA, Peptide, and Glycan Arrays: An Immunological Case Series.

Pathogens 2021 Apr 6;10(4). Epub 2021 Apr 6.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, 14476 Potsdam, Germany.

The current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). A better understanding of its immunogenicity can be important for the development of improved diagnostics, therapeutics, and vaccines. Here, we report the longitudinal analysis of three COVID-19 patients with moderate (#1) and mild disease (#2 and #3). Antibody serum responses were analyzed using spike glycoprotein enzyme linked immunosorbent assay (ELISA), full-proteome peptide, and glycan microarrays. ELISA immunoglobulin A, G, and M (IgA, IgG, and IgM) signals increased over time for individuals #1 and #2, whereas #3 only showed no clear positive IgG and IgM result. In contrast, peptide microarrays showed increasing IgA/G signal intensity and epitope spread only in the moderate patient #1 over time, whereas early but transient IgA and stable IgG responses were observed in the two mild cases #2 and #3. Glycan arrays showed an interaction of antibodies to fragments of high-mannose and core -glycans, present on the viral shield. In contrast to protein ELISA, microarrays allow for a deeper understanding of IgA, IgG, and IgM antibody responses to specific epitopes of the whole proteome and glycans of SARS-CoV-2 in parallel. In the future, this may help to better understand and to monitor vaccination programs and monoclonal antibodies as therapeutics.
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http://dx.doi.org/10.3390/pathogens10040438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067489PMC
April 2021

Discovery of Oligosaccharide Antigens for Semi-Synthetic Glycoconjugate Vaccine Leads against Streptococcus suis Serotypes 2, 3, 9 and 14*.

Angew Chem Int Ed Engl 2021 Jun 19;60(26):14679-14692. Epub 2021 May 19.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.

Streptococcus suis bacteria are one of the most serious health problems for pigs and an emerging zoonotic agent in humans working in the swine industry. S. suis bacteria express capsular polysaccharides (CPS) a major bacterial virulence factor that define the serotypes. Oligosaccharides resembling the CPS of S. suis serotypes 2, 3, 9, and 14 have been synthesized, glycans related to serotypes 2 and 9 were placed on glycan array surfaces to screen blood from infected pigs. Lead antigens for the development of semi-synthetic S. suis serotypes 2 and 9 glycoconjugate veterinary vaccines were identified in this way.
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http://dx.doi.org/10.1002/anie.202103990DOI Listing
June 2021

Discovery of Semi- and Fully-Synthetic Carbohydrate Vaccines Against Bacterial Infections Using a Medicinal Chemistry Approach.

Chem Rev 2021 Apr 1;121(7):3598-3626. Epub 2021 Apr 1.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces Am Mühlenberg 1, 14476 Potsdam, Germany.

The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against , type b, and infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against , , , and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.
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http://dx.doi.org/10.1021/acs.chemrev.0c01210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154330PMC
April 2021

Automated Glycan Assembly of F-labeled Glycan Probes Enables High-Throughput NMR Studies of Protein-Glycan Interactions.

Angew Chem Int Ed Engl 2021 Jun 7;60(24):13302-13309. Epub 2021 May 7.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.

Protein-glycan interactions mediate important biological processes, including pathogen host invasion and cellular communication. Herein, we showcase an expedite approach that integrates automated glycan assembly (AGA) of F-labeled probes and high-throughput NMR methods, enabling the study of protein-glycan interactions. Synthetic Lewis type 2 antigens were screened against seven glycan binding proteins (GBPs), including DC-SIGN and BambL, respectively involved in HIV-1 and lung infections in immunocompromised patients, confirming the preference for fucosylated glycans (Le , H type 2, Le ). Previously unknown glycan-lectin weak interactions were detected, and thermodynamic data were obtained. Enzymatic reactions were monitored in real-time, delivering kinetic parameters. These results demonstrate the utility of AGA combined with F NMR for the discovery and characterization of glycan-protein interactions, opening up new perspectives for F-labeled complex glycans.
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http://dx.doi.org/10.1002/anie.202102690DOI Listing
June 2021

Analysis of Synthetic Monodisperse Polysaccharides by Wide Mass Range Ultrahigh-Resolution MALDI Mass Spectrometry.

Anal Chem 2021 03 5;93(10):4666-4675. Epub 2021 Mar 5.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.

Carbohydrates, such as oligo- and polysaccharides, are highly abundant biopolymers that are involved in numerous processes. The study of their structure and functions is commonly based on a material that is isolated from complex natural sources. However, a more precise analysis requires pure compounds with well-defined structures that can be obtained from chemical or enzymatic syntheses. Novel synthetic strategies have increased the accessibility of larger monodisperse polysaccharides, posing a challenge to the analytical methods used for their molecular characterization. Here, we present wide mass range ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) as a powerful platform for the analysis of synthetic oligo- and polysaccharides. Synthetic carbohydrates 16-, 64-, 100-, and 151-mers were mass analyzed and characterized by MALDI in-source decay FT-ICR MS. Detection of fragment ions generated from glycosidic bond cleavage (or cross-ring cleavage) provided information of the monosaccharide content and the linkage type, allowing for the corroboration of the carbohydrate compositions and structures.
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http://dx.doi.org/10.1021/acs.analchem.1c00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034773PMC
March 2021

Zwitterionic Character and Lipid Composition Determine the Behaviour of Glycosylphosphatidylinositol Fragments in Monolayers.

Chemphyschem 2021 04 15;22(8):757-763. Epub 2021 Mar 15.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, 14476, Potsdam, Germany.

Glycosylphosphatidylinositols (GPIs) are complex glycolipids found in free form or anchoring proteins to the outer leaflet of the cell membrane in eukaryotes. GPIs have been associated with the formation of lipid rafts and protein sorting on membranes. The presence of a conserved glycan core with cell-specific modifications together with lipid remodelling during biosynthesis suggest that the properties of the glycolipids are being fine-tuned. We synthesized a series of GPI fragments and evaluated the interactions and arrangement of these glycolipids in monolayers as a 2-D membrane model. GIXD and IRRAS analyses showed the need of N-acetylglucosamine deacetylation for the formation of hydrogen bonds to obtain highly structured domains in the monolayers and an effect of the unsaturated lipids in formation and localization of the glycolipids within or between membrane microdomains. These results contribute to understand the role of these glycolipids and their modifications in the organization of membranes.
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http://dx.doi.org/10.1002/cphc.202100002DOI Listing
April 2021

Visible-Light-Mediated Oxidative Debenzylation Enables the Use of Benzyl Ethers as Temporary Protecting Groups.

Org Lett 2021 01 5;23(2):514-518. Epub 2021 Jan 5.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

The cleavage of benzyl ethers by catalytic hydrogenolysis or Birch reduction suffers from poor functional group compatibility and limits their use as a protecting group. The visible-light-mediated debenzylation disclosed here renders benzyl ethers temporary protective groups, enabling new orthogonal protection strategies. Using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as a stoichiometric or catalytic photooxidant, benzyl ethers can be cleaved in the presence of azides, alkenes, and alkynes. The reaction time can be reduced from hours to minutes in continuous flow.
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http://dx.doi.org/10.1021/acs.orglett.0c04026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880570PMC
January 2021

Systematic Structural Characterization of Chitooligosaccharides Enabled by Automated Glycan Assembly.

Chemistry 2021 Feb 7;27(7):2321-2325. Epub 2021 Jan 7.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.

Chitin, a polymer composed of β(1-4)-linked N-acetyl-glucosamine monomers, and its partially deacetylated analogue chitosan, are abundant biopolymers with outstanding mechanical as well as elastic properties. Their degradation products, chitooligosaccharides (COS), can trigger the innate immune response in humans and plants. Both material and biological properties are dependent on polymer length, acetylation, as well as the pH. Without well-defined samples, a complete molecular description of these factors is still missing. Automated glycan assembly (AGA) enabled rapid access to synthetic well-defined COS. Chitin-cellulose hybrid oligomers were prepared as important tools for a systematic structural analysis. Intramolecular interactions, identified by molecular dynamics simulations and NMR analysis, underscore the importance of the chitosan amino group for the stabilization of specific geometries.
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http://dx.doi.org/10.1002/chem.202005228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898498PMC
February 2021

Glycoconjugates for glucose transporter-mediated cancer-specific targeting and treatment.

Carbohydr Res 2020 Dec 12;498:108195. Epub 2020 Nov 12.

Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China. Electronic address:

First observed in 1920s, the Warburg effects have inspired scientists to harness the unique glucose metabolism of cancer cells for targeted therapy for a century. Carbohydrate-drug conjugates are explicitly designed for selective uptake by cancer cells overexpressing glucose transporters. We summarize the progress in developing glycoconjugates for cancer-specific targeting and treatment over the past decade (2010-2020) and point to some future directions in this field.
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http://dx.doi.org/10.1016/j.carres.2020.108195DOI Listing
December 2020

Gut microbiota-specific IgA B cells traffic to the CNS in active multiple sclerosis.

Sci Immunol 2020 11;5(53)

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
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http://dx.doi.org/10.1126/sciimmunol.abc7191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043673PMC
November 2020

Advances in the Chemical Synthesis of Carbohydrates and Glycoconjugates.

Adv Biochem Eng Biotechnol 2020 Nov 14. Epub 2020 Nov 14.

Max Planck Institute of Colloids and Interfaces, Biomolecular Systems, Potsdam, Germany.

Carbohydrates are functional and structural biomolecules with structures ranging from monosaccharides to polysaccharides. They are naturally found as pure glycans or attached to lipids and proteins forming glycoconjugates. The biosynthesis of carbohydrates is not genetically controlled. The regulation takes place by the expression of enzymes that transfer and hydrolyze the glycan units, leading to glycocojugates having complex mixtures of glycan structures. Chemical synthesis emerged as the best strategy to obtain defined glycan and glycoconjugates and overcome the challenging purification processes. Here, we review the recent advances in the synthesis of oligosaccharides using manual and automated methods. The chapter covers the methods for the preparation of building blocks and control of stereoselectivity and regioselectivity during glycosylations. Finally, it also presents the strategies to obtain natural and non-natural glycoconjugates with lipids and proteins.
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http://dx.doi.org/10.1007/10_2020_150DOI Listing
November 2020

Exploring the Molecular Conformation Space by Soft Molecule-Surface Collision.

J Am Chem Soc 2020 12 10;142(51):21420-21427. Epub 2020 Nov 10.

Max Planck Institute for Solid State Research, Heisenbergstrasse 1, Stuttgart DE-70569, Germany.

Biomolecules function by adopting multiple conformations. Such dynamics are governed by the conformation landscape whose study requires characterization of the ground and excited conformation states. Here, the conformational landscape of a molecule is sampled by exciting an initial gas-phase molecular conformer into diverse conformation states, using soft molecule-surface collision (0.5-5.0 eV). The resulting ground and excited molecular conformations, adsorbed on the surface, are imaged at the single-molecule level. This technique permits the exploration of oligosaccharide conformations, until now, limited by the high flexibility of oligosaccharides and ensemble-averaged analytical methods. As a model for cellulose, cellohexaose chains are observed in two conformational extremes, the typical "extended" chain and the atypical "coiled" chain-the latter identified as the gas-phase conformer preserved on the surface. Observing conformations between these two extremes reveals the physical properties of cellohexaose, behaving as a rigid ribbon that becomes flexible when twisted. The conformation space of any molecule that can be electrosprayed can now be explored.
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http://dx.doi.org/10.1021/jacs.0c09933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760097PMC
December 2020

Direct Experimental Characterization of the Ferrier Glycosyl Cation in the Gas Phase.

Org Lett 2020 11 5;22(22):8916-8919. Epub 2020 Nov 5.

Freie Universität Berlin, Institute of Chemistry and Biochemistry, 14195 Berlin, Germany.

The Ferrier rearrangement reaction is crucial for the synthesis of pharmaceuticals. Although its mechanism was described more than 50 years ago, the structure of the intermediate remains elusive. Two structures have been proposed for this Ferrier glycosyl cation: a 1,2-unsaturated cation that is resonance-stabilized within the pyranose ring or a cation that is stabilized by the anchimeric assistance of a neighboring acetyl group. Using a combination of gas-phase cryogenic infrared spectroscopy in helium nanodroplets and first-principles density functional theory, we provide the first direct structural characterization of Ferrier cations. The data show that both acetylated glucal and galactal lead to glycosyl cations of the dioxolenium type.
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http://dx.doi.org/10.1021/acs.orglett.0c03301DOI Listing
November 2020

How to approach flow chemistry.

Chem Soc Rev 2020 Dec 3;49(24):8910-8932. Epub 2020 Nov 3.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

Flow chemistry is a widely explored technology whose intrinsic features both facilitate and provide reproducible access to a broad range of chemical processes that are otherwise inefficient or problematic. At its core, a flow chemistry module is a stable set of conditions - traditionally thought of as an externally applied means of activation/control (e.g. heat or light) - through which reagents are passed. In an attempt to simplify the teaching and dissemination of this field, we envisioned that the key advantages of the technique, such as reproducibility and the correlation between reaction time and position within the reactor, allow for the redefinition of a flow module to a more synthetically relevant one based on the overall induced effect. We suggest a rethinking of the approach to flow modules, distributing them in two subclasses: transformers and generators, which can be described respectively as a set of conditions for either performing a specific transformation or for generating a reactive intermediate. The chemistry achieved by transformers and generators is (ideally) independent of the substrate introduced, meaning that they must be robust to small adjustments necessary for the adaptation to different starting materials and reagents while ensuring the same chemical outcome. These redefined modules can be used for single-step reactions or in multistep processes, where modules can be connected to each other in reconfigurable combinations to create chemical assembly systems (CAS) targeting compounds and libraries sharing structural cores. With this tutorial review, we provide a guide to the overall approach to flow chemistry, discussing the key parameters for the design of transformers and generators as well as the development of chemical assembly systems.
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http://dx.doi.org/10.1039/c9cs00832bDOI Listing
December 2020

Supramolecular Assembly and Chirality of Synthetic Carbohydrate Materials.

Angew Chem Int Ed Engl 2020 12 7;59(50):22577-22583. Epub 2020 Oct 7.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.

Hierarchical carbohydrate architectures serve multiple roles in nature. Hardly any correlations between the carbohydrate chemical structures and the material properties are available due to the lack of standards and suitable analytic techniques. Therefore, designer carbohydrate materials remain highly unexplored, as compared to peptides and nucleic acids. A synthetic D-glucose disaccharide, DD, was chosen as a model to explore carbohydrate materials. Microcrystal electron diffraction (MicroED), optimized for oligosaccharides, revealed that DD assembled into highly crystalline left-handed helical fibers. The supramolecular architecture was correlated to the local crystal organization, allowing for the design of the enantiomeric right-handed fibers, based on the L-glucose disaccharide, LL, or flat lamellae, based on the racemic mixture. Tunable morphologies and mechanical properties suggest the potential of carbohydrate materials for nanotechnology applications.
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http://dx.doi.org/10.1002/anie.202008153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756587PMC
December 2020

Targeting and Inhibiting Using Ultra-small Gold Nanoparticles.

ACS Appl Mater Interfaces 2020 Sep 16;12(39):43380-43387. Epub 2020 Sep 16.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

Malaria, a mosquito-borne disease caused by species, claims more than 400,000 lives globally each year. The increasing drug resistance of the parasite renders the development of new anti-malaria drugs necessary. Alternatively, better delivery systems for already marketed drugs could help to solve the resistance problem. Herein, we report glucose-based ultra-small gold nanoparticles (Glc-NCs) that bind to cysteine-rich domains of surface proteins Microscopy shows that Glc-NCs bind specifically to extracellular and all intra-erythrocytic stages of Glc-NCs may be used as drug delivery agents as illustrated for ciprofloxacin, a poorly soluble antibiotic with low antimalarial activity. Ciprofloxacin conjugated to Glc-NCs is more water-soluble than the free drug and is more potent. Glyco-gold nanoparticles that target cysteine-rich domains on parasites may be helpful for the prevention and treatment of malaria.
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http://dx.doi.org/10.1021/acsami.0c09075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586288PMC
September 2020

Sequential Linkage of Carbohydrate Antigens to Mimic Capsular Polysaccharides: Toward Semisynthetic Glycoconjugate Vaccine Candidates against Serotype 14.

ACS Chem Biol 2020 09 8;15(9):2395-2405. Epub 2020 Sep 8.

Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

Vaccines based on isolated polysaccharides successfully protect humans from bacterial pathogens such as . Because polysaccharide production and isolation can be technically challenging, glycoconjugates containing synthetic antigens are an attractive alternative. Typically, the shortest possible oligosaccharide antigen is preferable as syntheses of longer structures are more difficult and time-consuming. Combining several protective epitopes or polysaccharide repeating units as blocks by bonds other than glycosidic linkages would greatly reduce the synthetic effort if the immunological response to the polysaccharide could be retained. To explore this concept, we bridged the well-understood and immunologically potent RU of serotype 14 (ST14) with an aliphatic spacer and conjugated it to the carrier protein CRM197. Mice immunized with the spacer-bridged glycan conjugates produced high levels of specific antibodies after just one or two vaccine doses, while the tetrasaccharide repeating unit alone required three doses. The antibodies recognized specifically ST14 CPS, while no significant antibody levels were raised against the spacer or unrelated CPS. Synthetic vaccines generated antibodies with opsonic activity. Mimicking polysaccharides by coupling repeating unit antigens via an aliphatic spacer may prove useful also for the development of other glycoconjugate vaccine candidates, thereby reducing the synthetic complexity while enhancing a faster immune response.
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http://dx.doi.org/10.1021/acschembio.0c00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506939PMC
September 2020

Total synthesis of D-glycero-D-mannno-heptose 1β, 7-bisphosphate with 3-O-amyl amine linker and its monophosphate derivative.

Chin J Nat Med 2020 Aug;18(8):628-632

Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. Electronic address:

D-Glycero-D-mannno-heptose 1β, 7-bisphosphate (HBPβ) is an important intermediate for constructing the core structure of Gram-negative bacterial lipopolysaccharides and was reported as a pathogen-associated molecular pattern (PAMP) that regulates immune responses. HBPβ with 3-O-amyl amine linker and its monophosphate derivative D-glycero-D-mannno-heptose 7-phosphate (HP) with 1α-amyl amine linker have been synthesized as candidates for immunity study of HBPβ. The O3-amyl amine linker of heptose was installed by dibutyltin oxide-mediated regioselective alkylation under fine-tuned protecting condition. The stereoselective installation of 1β-phosphate ester was achieved by NIS-mediated phosphorylation at low temperature. The strategy for installation of 3-O-amyl amine linker onto HBP derivative can be expanded to the syntheses of other conjugation-ready carbohydrates bearing anomeric phosphoester.
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http://dx.doi.org/10.1016/S1875-5364(20)30075-3DOI Listing
August 2020

Chemical Synthesis Elucidates the Key Antigenic Epitope of the Autism-Related Bacterium Clostridium bolteae Capsular Octadecasaccharide.

Angew Chem Int Ed Engl 2020 11 2;59(46):20529-20537. Epub 2020 Sep 2.

Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu Province, 214122, P. R. China.

The gut pathogen Clostridium bolteae has been associated with the onset of autism spectrum disorder (ASD). To create vaccines against C. bolteae, it is important to identify exact protective epitopes of the immunologically active capsular polysaccharide (CPS). Here, a series of C. bolteae CPS glycans, up to an octadecasaccharide, was prepared. Key to achieving the total syntheses is a [2+2] coupling strategy based on a β-d-Rhap-(1→3)-α-d-Manp repeating unit that in turn was accessed by a stereoselective β-d-rhamnosylation. The 4,6-O-benzylidene-induced conformational locking is a powerful strategy for forming a β-d-mannose-type glycoside. An indirect strategy based on C2 epimerization of β-d-quinovoside was efficiently achieved by Swern oxidation and borohydride reduction. Sequential glycosylation, and regioselective and global deprotection produced the disaccharide and tetrasaccharide, up to the octadecasaccharide. Glycan microarray analysis of sera from rabbits immunized with inactivated C. bolteae bacteria revealed a humoral immune response to the di- and tetrasaccharide, but none of the longer sequences. The tetrasaccharide may be a key motif for designing glycoconjugate vaccines against C. bolteae.
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http://dx.doi.org/10.1002/anie.202007209DOI Listing
November 2020

Synthesis of serotype 9V oligosaccharide antigens.

Beilstein J Org Chem 2020 15;16:1693-1699. Epub 2020 Jul 15.

Max Planck Institute of Colloids and Interfaces, Biomolecular Systems Department, Am Mühlenberg 1, 14476 Potsdam, Germany.

(SP) bacteria cause serious invasive diseases. SP bacteria are covered by a capsular polysaccharide (CPS) that is a virulence factor and the basis for SP polysaccharide and glycoconjugate vaccines. The serotype 9V is part of the currently marketed conjugate vaccine and contains an acetate modification. To better understand the importance of glycan modifications in general and acetylation in particular, defined oligosaccharide antigens are needed for serological and immunological studies. Here, we demonstrate a convergent [2 + 3] synthetic strategy to prepare the pentasaccharide repeating unit of 9V with and without an acetate group at the C-6 position of mannosamine.
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http://dx.doi.org/10.3762/bjoc.16.140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372248PMC
July 2020

The Impact of Leaving Group Anomericity on the Structure of Glycosyl Cations of Protected Galactosides.

Chemphyschem 2020 09 30;21(17):1905-1907. Epub 2020 Jul 30.

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195, Berlin, Germany.

It has been reported that fragments produced by glycosidic bond breakage in mass spectrometry-based experiments can retain a memory of their anomeric configuration, which has major implications for glycan sequencing. Herein, we use cryogenic vibrational spectroscopy and ion mobility-mass spectrometry to study the structure of B-type fragments of protected galactosides. Cationic fragments were generated from glycosyl donors carrying trichloroacetimidate or thioethyl leaving groups of different anomeric configuration. The obtained infrared signatures indicate that the investigated fragments exhibit an identical structure, which suggests that there is no anomeric memory in B-type ions of fully protected monosaccharides.
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http://dx.doi.org/10.1002/cphc.202000473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540451PMC
September 2020

Glycan-dependent cell adhesion mechanism of Tc toxins.

Nat Commun 2020 06 1;11(1):2694. Epub 2020 Jun 1.

Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.

Toxin complex (Tc) toxins are virulence factors of pathogenic bacteria. Tcs are composed of three subunits: TcA, TcB and TcC. TcA facilitates receptor-toxin interaction and membrane permeation, TcB and TcC form a toxin-encapsulating cocoon. While the mechanisms of holotoxin assembly and pore formation have been described, little is known about receptor binding of TcAs. Here, we identify heparins/heparan sulfates and Lewis antigens as receptors for different TcAs from insect and human pathogens. Glycan array screening reveals that all tested TcAs bind negatively charged heparins. Cryo-EM structures of Morganella morganii TcdA4 and Xenorhabdus nematophila XptA1 reveal that heparins/heparan sulfates unexpectedly bind to different regions of the shell domain, including receptor-binding domains. In addition, Photorhabdus luminescens TcdA1 binds to Lewis antigens with micromolar affinity. Here, the glycan interacts with the receptor-binding domain D of the toxin. Our results suggest a glycan dependent association mechanism of Tc toxins on the host cell surface.
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http://dx.doi.org/10.1038/s41467-020-16536-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264150PMC
June 2020

Evidence for Photocatalyst Involvement in Oxidative Additions of Nickel-Catalyzed Carboxylate -Arylations.

J Am Chem Soc 2020 06 11;142(25):11042-11049. Epub 2020 Jun 11.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.

Dual photocatalysis and nickel catalysis can effect cross-coupling under mild conditions, but little is known about the kinetics of this class of reactions. We report a comprehensive kinetic examination of a model carboxylate -arylation, comparing a state-of-the-art homogeneous photocatalyst (Ir(ppy)) with a competitive heterogeneous photocatalyst (graphitic carbon nitride). Experimental conditions were adjusted such that the nickel catalytic cycle is saturated with excited photocatalyst. This approach was designed to remove the role of the photocatalyst, by which only the intrinsic behaviors of the nickel catalytic cycles are observed. The two reactions did not display identical kinetics. Ir(ppy) deactivates the nickel catalytic cycle and creates more dehalogenated side product. Kinetic data for the reaction using Ir(ppy) supports a turnover-limiting reductive elimination. Graphitic carbon nitride gave higher selectivity, even at high photocatalyst-to-nickel ratios. The heterogeneous reaction also showed a rate dependence on aryl halide, indicating that oxidative addition plays a role in rate determination. The results argue against the current mechanistic hypothesis, which states that the photocatalyst is only involved to trigger reductive elimination.
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http://dx.doi.org/10.1021/jacs.0c02848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467672PMC
June 2020