Inhibition of DC-SIGN-Mediated HIV Infection by a Linear Trimannoside Mimic in a Tetravalent Presentation

Abstract

HIV infection is pandemic in humans and is responsible for millions of deaths every year. The discovery of new cellular targets that can be used to prevent the infection process represents a new opportunity for developing more effective antiviral drugs. In this context, dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), a lectin expressed at the surface of immature dendritic cells and involved in the initial stages of HIV infection, is a promising therapeutic target. Herein we show the ability of a new tetravalent dendron containing four copies of a linear trimannoside mimic to inhibit the trans HIV infection process of CD4+ T lymphocytes at low micromolar range. This compound presents a high solubility in physiological media, a neglectable cytotoxicity, and a long-lasting effect and is based on carbohydrate-mimic units. Notably, the HIV antiviral activity is independent of viral tropism (X4 or R5). The formulation of this compound as a gel could allow its use as topical microbicide.

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].…”

Glycodendritic structures: tools to interact with DC-SIGN

“…Two scaffolds with different valency were synthesized: a tetravalent dendron and a 3 rd generation Boltorn-type dendrimer, both being monodisperse compounds. The corresponding tetravalent glycodendrons 3 and 4, and the multivalent glycodendrimers 5 and 6 (Figure 7) were evaluated as potential inhibitors of DC-SIGN (Sattin et al, 2010).…”

“…Infection was abrogated almost totally by 4 at 100 mM concentration, and an IC 50 ca. 10 mM could be estimated (Sattin et al, 2010), a very promising value as starting point to define better antiviral compounds. Furthermore, dendron 4 was evaluated as a suitable candidate for the development as topical HIV microbicide (Berzi et al, 2012).…”

Carbohydrate Mimics and Lectins: A Source of New Drugs and Therapeutic Opportunities

“…45 This compound inhibits DC-SIGN binding to mannosylated BSA (Bovine serum albumin) with an IC50 of 130 M (by surface-plasmon resonance, SPR). 46 The affinity for DC-SIGN of both these monovalent ligands is too weak for them to represent effective inhibitors of DC-SIGN-mediated infections and their therapeutic potential is limited. However, appropriate levels of affinity have been obtained when the ligands were presented in a multimeric form.…”

“…However, appropriate levels of affinity have been obtained when the ligands were presented in a multimeric form. 46,47 The multimeric presentation of the glycomimetics 1 and 2 were synthesized by conjugation of the monovalent ligands to tetra-and multivalent scaffolds based on bishydroxymethylpropionic acid as building block. Tetravalent presentation of the pseudotrisaccharide 2 in dendron 3 (Figure 2) was shown to inhibit trans infection of T lymphocytes by DC-SIGN expressing B-cells, which had been pre-incubated with HIV in the presence of 3.…”