Selective Inhibition of Sialic Acid-Based Molecular Mimicry in Haemophilus influenzae Abrogates Serum Resistance

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Fluorinated Mannosides Inhibit Cellular Fucosylation.

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation

Cellular Fucosylation Inhibitors Based on Fluorinated Fucose-1-phosphates**

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Cellular Fucosylation Inhibitors Based on Fluorinated Fucose-1-Phosphates

Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2-fluorofucose 1-phosphate efficiently inhibits cellular fucosylation with a four to seven times higher potency than known inhibitor 2FF, independently of the anomeric stereochemistry. Nucleotide sugar analysis revealed that both the α- and β-GDP-2FF anomers are formed inside the cell. In conclusion, we developed A2FF1P and B2FF1P as potent new tools for studying the role of fucosylation in health and disease and they are potential therapeutic candidates

Modular synthesis and immunological evaluation of suspected allergenic galactooligosaccharides

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Luminescent Assay for the Screening of SARS-CoV-2 MPro Inhibitors

Since the outbreak of SARS-CoV-2 in December 2019 millions of infections have been reported globally. The viral chymotrypsin-like main protease (MPro) exhibits a crucial role in viral replication and represents a relevant target for antiviral drug development. In order to screen potential MPro inhibitors we developed a luminescent assay using a peptide based probe containing a cleavage site specific for MPro. This assay was validated showing IC50 values similar to those reported in the literature for known MPro inhibitors and can be used to screen new inhibitors

Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs

Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of sugar metabolites in organisms and in model cells and identified novel low abundant nucleotide sugars in human cells, such as ADP-glucose and UDP-arabinose, and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Dynamic tracing of propargyloxycarbonyl (Poc) labeled analogs, commonly used for MOE, revealed that ManNPoc is metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, combined treatment of B16-F10 melanoma cells with antitumor compound 3Fax-NeuNAc and 13C-labeled GlcNAc revealed that endogenous CMP-NeuNAc levels started to decrease before a subsequent decrease of ManNAc 6-phosphate was observed. This implicates 3Fax-NeuNAc first acts as a substrate for cytosolic CMP-sialic acid synthetase and subsequently its product CMP-3Fax-NeuNAc functions as a feed-back inhibitor for UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Thus, dynamic analysis of sugar metabolites provides key insights into the time-dependent metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects