Host-derived O-glycans inhibit toxigenic conversion by a virulence-encoding phage in Vibrio cholerae.

Pandemic and endemic strains of Vibrio cholerae arise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains of V. cholerae. CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections.

Synthesis of Mucin O-Glycans Associated with Attenuation of Pathogen Virulence.

With the concerning rise in antibiotic-resistant infections, novel treatment options against pathogens are urgently sought. Several recent studies have identified mucin O-glycan mixtures as potent down-regulators of virulence-related gene expression in diverse pathogens. As individual mucin glycans cannot be isolated in sufficient purity and quantity for biological evaluation of discrete structures, we have developed an optimized synthetic approach to generate a small library of mucin glycans which were identified as most likely to display activity.

Mucin O-glycans are natural inhibitors of Candida albicans pathogenicity.

Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans.

Swiss Women in Chemistry - Two Years Later ..

The SCS Swiss Women in Chemistry network was launched in September 2019. Under the umbrella of the Swiss Chemical Society, its aim is to create visibility, facilitate networking and provide a supportive community for female chemists in Switzerland across all career stages both in industry and academia. The current article provides an overview on the platform's activities over the past two years.

The Role of Fluorine in Glycomimetic Drug Design.

Glycans are well established to play important roles at various stages of infection and disease, and ways to modulate these interactions have been sought as novel therapies. The use of native glycan structures has met with limited success, which can be attributed to their characteristic high polarity (e.g.

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design.

The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties.

Strategies for the Development of Glycomimetic Drug Candidates.

Carbohydrates are a structurally-diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Many diseases have been correlated with changes in the composition of cell-surface glycans, highlighting their potential as a therapeutic target. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties.

Dynamic Combinatorial Chemistry: A New Methodology Comes of Age.

Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands.

What contributes to an effective mannose recognition domain?

In general, carbohydrate-lectin interactions are characterized by high specificity but also low affinity. The main reason for the low affinities are desolvation costs, due to the numerous hydroxy groups present on the ligand, together with the typically polar surface of the binding sites. Nonetheless, nature has evolved strategies to overcome this hurdle, most prominently in relation to carbohydrate-lectin interactions of the innate immune system but also in bacterial adhesion, a process key for the bacterium's survival.

Total Synthesis of β-d-ido-Heptopyranosides Related to Capsular Polysaccharides of Campylobacter jejuni HS:4.

The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is very remarkable, owing to the unique, multifaceted structural features that have been combined into one molecule, which include (1) the rare ido-configuration, (2) the unusual 7-carbon backbone, and (3) the challenging β-(1→2)-cis-anomeric configuration. Two distinct strategies toward the total synthesis of this interesting target are reported.

Studies on the 6-homologation of β-D-idopyranosides.

β-D-Idopyranosides are interesting sugars because of their unusual conformational flexibility in the pyranosyl ring, and also their β-1,2-cis-anomeric configuration. Here we report our studies of the regioselective opening of 4,6-O-benzylidene-protected β-D-idopyranosides under reducing conditions, and the subsequent 6-homologation via Swern oxidation and Wittig olefination to afford a 6,7-dideoxy-β-D-ido-hept-6-enopyranoside. This olefination product was found to adopt predominantly C conformation in solution by NMR experiments, which places the vinyl group at a more sterically hindered axial position and creates difficulty in subsequent hydroborations.

Recent advances toward the development of inhibitors to attenuate tumor metastasis via the interruption of lectin-ligand interactions.

Aberrant glycosylation is a well-recognized phenomenon that occurs on the surface of tumor cells, and the overexpression of a number of ligands (such as TF, sialyl Tn, and sialyl Lewis X) has been correlated to a worse prognosis for the patient. These unique carbohydrate structures play an integral role in cell-cell communication and have also been associated with more metastatic cancer phenotypes, which can result from binding to lectins present on cell surfaces. The most well studied metastasis-associated lectins are the galectins and selectins, which have been correlated to adhesion, neoangiogenesis, and immune-cell evasion processes.

Role of the 4,6-O-acetal in the regio- and stereoselective conversion of 2,3-di-O-sulfonyl-β-D-galactopyranosides to D-idopyranosides.

The recently reported conversion of 2,3-di-O-sulfonyl-D-galactopyranosides to D-idopyranosides has provided an efficient route to obtaining orthogonally-protected idopyranoside building blocks with a β-1,2-cis glycosidic linkage. In an effort to expand the scope of this process and better understand the regio- and stereoselectivity observed in the key di-inversion step of the method, a small library of 4,6-O-acetal protected galactopyranosides has been synthesized and used as substrates in the process, together with a number of substrates that lack the acetal functionality. The results suggest that although the substituent at the acetal center does not contribute to the observed selectivity of the process, the acetal group is indeed required for efficient conversion by reducing the conformational flexibility of the substrate, resulting in enhanced reaction rates at both the O-transsulfonylation and epoxide ring-opening steps.

Evidence of cation-coordination involvement in directing the regioselective di-inversion reaction of vicinal di-sulfonate esters.

Direct evidence has been obtained to confirm the unusual nucleophilic attack of an alkoxide at the S-center of sp(3)-hybridized sulfonyl esters. The unusual reaction pathway leads to S-O bond scission which is crucial for the regio- and stereoselective conversion of 2,3-di-O-sulfonates of 4,6-O-benzylidene-β-D-galactopyranosides into β-D-idopyranosides. In addition, strong evidence has been provided to clarify the role of the alkali counter-cation in the transformation.

A scalable approach to obtaining orthogonally protected β-D-idopyranosides.

A practical method to obtain orthogonally protected D-idopyranose from D-galactose has been developed, which is the first method to enable synthesis of the challenging β-D-idopyranoside linkage. The method relies on a key double inversion at O-2 and O-3 in an easily prepared D-galactose derivative, which proceeds regio- and stereoselectively through a 2,3-anhydrotalopyranoside; reaction using a selection of alkoxides affords exclusively the 3-O-alkylidopyranoside, which can be used to generate an orthogonally protected monosaccharide. The process is scalable and requires minimal purification, so it could be used to produce building blocks to aid in the synthesis of various β-idopyranose-containing oligosaccharide targets to further probe their biological functions.

Recent advances in developing synthetic carbohydrate-based vaccines for cancer immunotherapies.

Cancer cells can often be distinguished from healthy cells by the expression of unique carbohydrate sequences decorating the cell surface as a result of aberrant glycosyltransferase activity occurring within the cell; these unusual carbohydrates can be used as valuable immunological targets in modern vaccine designs to raise carbohydrate-specific antibodies. Many tumor antigens (e.g.

Synthesis of a Forssman antigen derivative for use in a conjugate vaccine.

The total chemical synthesis of a Forssman antigen analog is described. The pentasaccharide contains a functionalized tether which should facilitate future conjugation with immunogenic proteins. We found that the total synthesis can be efficiently achieved by following a convergent 2+3 strategy, and using N-Troc protected GalNAc thioglycoside as a donor.