Synthesis of the Aliphatic Subunit of the Macrolide LL‐Z 1640‐2 via Vasella Ring Opening of a 6‐Iodo‐4‐deoxy‐D‐mannose

The synthesis of the aliphatic subunit 9 of the macrolide LL‐Z1640‐2 (I), starting from a 4‐deoxy‐D‐mannose derivative 2a, is described. The procedure includes the first successful application of a Vasella ring opening reaction for a 4‐deoxypyranoside. Nucleophilic addition of an alkynyllithium reagent to the aldehyde 4 led to the propargylic alcohol 7, which was converted to the advanced building block 9 in two further steps.     

A Multivalent Ligand for the Mannose‐6‐Phosphate Receptor for Endolysosomal Targeting of an Activity‐Based Probe

The ubiquitously expressed mannose‐6‐phosphate receptors (MPRs) are a promising class of receptors for targeted compound delivery into the endolysosomal compartments of a variety of cell types. The development of a synthetic, multivalent, mannose‐6‐phosphate (M6P) glycopeptide‐based MPR ligand is described. The conjugation of this ligand to fluorescent DCG‐04, an activity‐based probe for cysteine cathepsins, enabled fluorescent readout of its receptor‐targeting properties. The resulting M6P‐cluster–BODIPY–DCG‐04 probe was shown to efficiently label cathepsins in cell lysates as well as in live cells. Furthermore, the introduction of the 6‐O‐phosphates leads to a completely altered uptake profile in COS and dendritic cells compared to a mannose‐containing ligand. Competition with mannose‐6‐phosphate abolished all uptake of the probe in COS cells, and we conclude that the mannose‐6‐phosphate cluster targets the MPR and ensures the targeted delivery of cargo bound to the cluster into the endolysosomal pathway.     

Construction of a High‐Mannose‐Type Glycan Library by a Renewed Top‐Down Chemo‐Enzymatic Approach

A comprehensive method for the construction of a high‐mannose‐type glycan library by systematic chemo‐enzymatic trimming of a single Man9‐based precursor was developed. It consists of the chemical synthesis of a non‐natural tridecasaccharide precursor, the orthogonal demasking of the non‐reducing ends, and trimming by glycosidases, which enabled a comprehensive synthesis of high‐mannose‐type glycans in their mono‐ or non‐glucosylated forms. It employed glucose, isopropylidene, and N‐acetylglucosamine groups for blocking the A‐, B‐, and C‐arms, respectively. After systematic trimming of the precursor, thirty‐seven high‐mannose‐type glycans were obtained. The power of the methodology was demonstrated by the enzymatic activity of human recombinant N‐acetylglucosaminyltransferase‐I toward M7–M3 glycans, clarifying the substrate specificity in the context of high‐mannose‐type glycans.     

O‐Mannosylation Affords a Glycopeptide Hydrogel with Inherent Antibacterial Activities against E. coli via Multivalent Interactions between Lectins and Supramolecular Assemblies

Multivalent carbohydrate–lectin interactions play a crucial role in bacterial infection. Biomimicry of multivalent glycosystems represents a major strategy in the repression of bacterial growth. In this study, a new kind of glycopeptide (Naphthyl‐Phe‐Phe‐Ser‐Tyr, NMY) scaffold with mannose modification is designed and synthesized, which is able to perform supramolecular self‐assembly with the assistance of catalytic enzyme, and present multiple mannose ligands on its self‐assembled structure to target mannose‐binding proteins. Relying on multivalent carbohydrate–lectin interactions, the glycopeptide hydrogel is able to bind Escherichia coli (E. coli) in high specificity, and result in bacterial adhesion, membrane disruption and subsequent cell death. In vivo wound healing assays reveal that this glycopeptide hydrogel exhibits considerable potentials for promoting wound healing and preventing E. coli infection in a full‐thickness skin defect mouse model. Therefore, through a specific mannose–lectin interaction, a biocompatible hydrogel with inherent antibacterial activity against E. coli is achieved without the need to resort to antibiotic or antimicrobial agent treatment, highlighting the potential role of sugar‐coated nanomaterials in wound healing and control of bacterial pathogenesis.     

Formation of the main degradation compounds from arabinose,xylose, mannose and arabinitol during pyrolysis

The thermochemical behaviour of sugars (D- and DL-arabinose, D- and DL-xylose and D-mannose) and sugar alcohol (D- and DL-arabinitol) was investigated by TG and pyrolysis-gas chromatography with mass-selective detection (Py-GC/MSD). The temperature of pyrolysis was 500 and 550°C. The TG-curves were measured both in air and nitrogen atmospheres, from 25 to 700°C with the heating rate of 2°C min^-1. In each case, the main pyrolysis products were classified into the following compound groups: (i) furanes, (ii) pyranes, (iii) cyclopentanes, (iv) cyclohexanes, (v) anhydroglucopyranoses, (vi) dianhydroglucopyranoses and (vii) saturated fatty acids. For example, the main peaks of the chromatograms of pentoses (arabinose, xylose), hexose (mannose) and sugar alcohols (arabinitols) were different. The greatest peak of pentoses in gas-chromatogram was 2-furancarboxaldehyde and that of hexose was (2H)-furan-3-one. The greatest peak of arabinitols at pyrolysis temperature of 500°C was furan methanol and at 550°C a-angeligalactone. 5-hydroxymethyl-2-furan carboxaldehyde was found only in the pyrolysis of D-mannose (hexose). The former study showed that it was not found in pyrolysis of pentoses. The amount of CO₂ and H₂O was not determined. This revised version was published online in July 2006 with corrections to the Cover Date.     

Gold Manno‐Glyconanoparticles: Multivalent Systems to Block HIV‐1 gp120 Binding to the Lectin DC‐SIGN

The HIV envelope glycoprotein gp120 takes advantage of the high‐mannose clusters on its surface to target the C‐type lectin dendritic cell‐specific intracellular adhesion molecule‐3‐grabbing non‐integrin (DC‐SIGN) on dendritic cells. Mimicking the cluster presentation of oligomannosides on the virus surface is a strategy for designing carbohydrate‐based antiviral agents. Bio‐inspired by the cluster presentation of gp120, we have designed and prepared a small library of multivalent water‐soluble gold glyconanoparticles (manno‐GNPs) presenting truncated (oligo)mannosides of the high‐mannose undecasaccharide Man₉GlcNAc₂ and have tested them as inhibitors of DC‐SIGN binding to gp120. These glyconanoparticles are ligands for DC‐SIGN, which also interacts in the early steps of infection with a large number of pathogens through specific recognition of associated glycans. (Oligo)mannosides endowed with different spacers ending in thiol groups, which enable attachment of the glycoconjugates to the gold surface, have been prepared. manno‐GNPs with different spacers and variable density of mannose (oligo)saccharides have been obtained and characterized. Surface plasmon resonance (SPR) experiments with selected manno‐GNPs have been performed to study their inhibition potency towards DC‐SIGN binding to gp120. The tested manno‐GNPs completely inhibit the binding from the micro‐ to the nanomolar range, while the corresponding monovalent mannosides require millimolar concentrations. manno‐GNPs containing the disaccharide Manα1‐2Manα are the best inhibitors, showing more than 20 000‐fold increased activity (100 % inhibition at 115 nM ) compared to the corresponding monomeric disaccharide (100 % inhibition at 2.2 mM ). Furthermore, increasing the density of dimannoside on the gold platform from 50 to 100 % does not improve the level of inhibition.     

Mannose‐Modified Serum Exosomes for the Elevated Uptake to Murine Dendritic Cells and Lymphatic Accumulation

The surface of bovine serum‐derived exosomes (EXOs) are modified with α‐d ‐mannose for facile interaction with mannose receptors on dendritic cells (DCs) and for efficient delivery of immune stimulators to the DCs. The surface of the EXOs is modified with polyethylene glycol (PEG) without particle aggregation (≈50 nm) via the incorporation of 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE) into the lipid layer of the EXO, compared to chemical conjugation by N‐hydroxysuccinimide activated PEG (NHS‐PEG). PEG modification onto the exosomal surface significantly decreases the non‐specific cellular uptake of the EXOs into the DCs. However, the EXOs with mannose‐conjugated PEG‐DSPE (EXO‐PEG‐man) exhibit excellent intracellular uptake into the DCs and boost the immune response by the incorporation of adjuvant, monophosphoryl lipid A (MPLA) within the EXO. After an intradermal injection, a higher retention of EXO‐PEG‐man is observed in the lymph nodes, which could be used for the efficient delivery of immune stimulators and antigens to the lymph nodes in vivo.