Structure of a Glycomimetic Ligand in the Carbohydrate Recognition Domain of C-type Lectin DC-SIGN. Structural Requirements for Selectivity and Ligand Design

Abstract

In genital mucosa, different fates are described for HIV according to the subtype of dendritic cells (DCs) involved in its recognition. This notably depends on the C-type lectin receptor, langerin or DC-SIGN, involved in gp120 interaction. Langerin blocks HIV transmission by its internalization in specific organelles of Langerhans cells. On the contrary, DC-SIGN enhances HIV trans-infection of T lymphocytes. Thus, approaches aiming to inhibit DC-SIGN, without blocking langerin, represent attractive anti-HIV strategies. We previously demonstrated that dendrons bearing multiple copies of glycomimetic compounds were able to block DC-SIGN-dependent HIV infection in cervical explant models. Optimization of such ligand requires detailed characterization of its binding mode. In the present work, we determined the first high-resolution structure of a glycomimetic/DC-SIGN complex by X-ray crystallography. This glycomimetic, pseudo-1,2-mannobioside, shares shape and conformational properties with Manα1-2Man, its natural counterpart. However, it uses the binding epitope previously described for Lewis X, a ligand specific for DC-SIGN among the C-type lectin family. Thus, selectivity gain for DC-SIGN versus langerin is observed with pseudo-1,2-mannobioside as shown by surface plasmon resonance analysis. In parallel, ligand binding was also analyzed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol. These studies demonstrate that the complex, defined by X-ray crystallography, represents the unique binding mode of this ligand as opposed to the several binding orientations described for the natural ligand. This exclusive binding mode and its selective interaction properties position this glycomimetic as a good lead compound for rational improvement based on a structurally driven approach.

Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators

“…But virus in the infected cells presumably have not replicated because (1) the B-THP-1/DC-SIGN cell line is almost identical to the Raji/DC-SIGN 14 and (2) endocytosis of HIV in Raji/DC-SIGN cells is not observed and they are not permissive to HIV infection. 15 While the fact that Raji/DC-SIGN cells are not permissive for HIV is well proven, 15 another work more convincingly shows most of HIV gp120 is internalized in Raji/DC-SIGN cells while a smaller share stays bound on the cell surface and the ratio conforms to our data. 16 The increase of virus-per-cell number between 2 and 24 h may be explained mainly by upregulation of DC-SIGN expression by HIV, 17 but not its replication.…”

“…12 Inhibitors of HIV infection and transinfection via the DC-SIGN lectin receptor have been tested only in preclinical studies. [13][14][15] Development or application of known drugs for the inhibition of HIV/DC-SIGN interaction may help in decreasing transinfection of T cells and in preventing the infection of DCs that serve as a long-term reservoir of HIV.…”

“…DC-SIGN inhibitors are of special interest as a means of preventing DC infection and CD4 + T cell transinfection by HIV. Many potential DC-SIGN inhibitors are in various stages of research, [13][14][15] and approaches for the high-throughput screening of potential inhibitors are being developed. 37 Our earlier studies on human macrophages 38 demonstrate that dextrans are also inhibitors of the interaction of HIV with another C-type lectin MR (CD206).…”

A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus

“…Thus, selective DC-SIGN ligands that interact only weakly with Langerin are actively sought after as potentially useful therapeutic tools against HIV and other viruses that use DC-SIGN as a primary receptor. [12][13][14][15] DC-SIGN is a tetramer and is organized into clustered patches at the cell membrane. [16,17] Interactions with pathogens, also expressing multiple copies of clustered glycans, involve a complex equilibrium that implies multipoint attachments.…”

Glycoconjugates and Glycomimetics as Microbial Anti-Adhesives

“…They both contain a terminal mannose residue connected to a conformationally locked cyclohexanediol [67] that mimics a mannose unit -α-1,2-substituted. Both 30 and 31 bind to the Ca ++ ion in DC-SIGN binding site using the non-reducing end residue (X-ray: [68,69]), inhibit DC-SIGN binding to mannosylated BSA [70], display a measurable selectivity [68,71] against Langerin, are not cyototoxic and are active in the Ebola infection model. The pseudo-trisaccharide 31 was the first of these antagonists to be formulated in polyvalent presentations: the tetravalent-Boltorn-type dendron 32 in low micromolar concentrations was shown to block DC-SIGN mediated HIV infection both in cellular and cervical explant models [70,71].…”