Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands.

Targeting C-type lectin receptors with multivalent carbohydrate ligands

Synthetic mRNAs can become biopharmaceutics allowing vaccination against cancer, bacterial and virus infections. Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Although immune responses are generated by naked mRNAs, their formulations with chemical carriers are expected to provide more specificity and internalization in dendritic cells (DCs) for better immune responses and dose reduction. This review reports lipid-based formulations (LBFs) that have proved preclinical efficacy. The selective delivery of mRNA LBFs to favor intracellular accumulation in DCs and reduction of the effective doses is discussed, notably to decorate LBFs with carbohydrates or glycomimetics allowing endocytosis in DCs. We also report how smart intracellular delivery is achieved using pH-sensitive lipids or polymers for an efficient mRNA escape from endosomes and limitations regarding cytosolic mRNA location for translation.

Lipid-based mRNA vaccine delivery systems

The Immune Nature of Platelets Revisited.

Ligand polyvalency is a powerful modulator of protein-receptor interactions. Host-pathogen infection interactions are often mediated by glycan ligand-protein interactions, yet its interrogation with very high copy number ligands has been limited to heterogenous systems. Here we report that through the use of nested layers of multivalency we are able to assemble the most highly valent glycodendrimeric constructs yet seen (bearing up to 1,620 glycans). These constructs are pure and well-defined single entities that at diameters of up to 32 nm are capable of mimicking pathogens both in size and in their highly glycosylated surfaces. Through this mimicry these glyco-dendri-protein-nano-particles are capable of blocking (at picomolar concentrations) a model of the infection of T-lymphocytes and human dendritic cells by Ebola virus. The high associated polyvalency effects (β>10(6), β/N ~10(2)-10(3)) displayed on an unprecedented surface area by precise clusters suggest a general strategy for modulation of such interactions.

https://users.ox.ac.uk/~dplb0149/publication/pub179.pdf

Virus-like glycodendrinanoparticles displaying quasi-equivalent nested polyvalency upon glycoprotein platforms potently block viral infection

DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLR) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand 2.

/pdf/detection-and-quantitative-analysis-of-two-independent-2d52g1uk7y.pdf

Detection and Quantitative Analysis of Two Independent Binding Modes of a Small Ligand Responsible for DC-SIGN Clustering

DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (LeX). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection.

/pdf/second-generation-of-fucose-based-dc-sign-ligands-affinity-2e6hx9vln2.pdf

Second generation of fucose-based DC-SIGN ligands: affinity improvement and specificity versus Langerin.

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Detection and Quantitative Analysis of Two Independent Binding Modes of a Small Ligand Responsible for DC-SIGN Clustering

Second generation of fucose-based DC-SIGN ligands: affinity improvement and specificity versus Langerin.