Macarena Sánchez-Navarro

MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery

Abstract Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

Fullerene sugar balls

Fullerene hexakis-adducts bearing 12 peripheral carbohydrate moieties have been prepared by grafting sugar derivatives onto the fullerene core through the copper mediated Huisgen 1,3-dipolar cycloaddition of azides and alkynes.

Inhibition of DC-SIGN-mediated HIV infection by a linear trimannoside mimic in a tetravalent presentation

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.

Glycofullerenes inhibit viral infection.

Water-soluble glycofullerenes based on a hexakis-adduct of [60]fullerene with an octahedral addition pattern are very attractive compounds providing a spherical presentation of carbohydrates. These tools have been recently described and they have been used to interact with lectins in a multivalent manner. Here, we present the use of these glycofullerenes, including new members with 36 mannoses, as compounds able to inhibit a DC-SIGN-dependent cell infection by pseudotyped viral particles. The results obtained in these experiments demonstrate for the first time that these glycoconjugates are adequate to inhibit efficiently an infection process, and therefore, they can be considered as very promising and interesting tools to interfere in biological events where lectins such as DC-SIGN are involved.

Pseudosaccharide Functionalized Dendrimers as Potent Inhibitors of DC-SIGN Dependent Ebola Pseudotyped Viral Infection

The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN.

[60]Fullerene as Multivalent Scaffold: Efficient Molecular Recognition of Globular Glycofullerenes by Concanavalin A

Financial support by the MICINN of Spain (CTQ2008-00795/BQU, CTQ2008-01694), the CAM (MADRISOLAR-2 S2009/PPQ-1533), Consolider- Ingenio (CSD2007-00010, Nanociencia Molecular), and the EU (FUNMOL FP7-212942-1) is greatly appreciated. A.M. thanks the MICINN for an FPI Studentship

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

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>106, β/N ~102–103) displayed on an unprecedented surface area by precise clusters suggest a general strategy for modulation of such interactions.

A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models

Objective:Dendritic cell-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) participates in the initial stages of sexually transmitted HIV-1 infection by recognizing highly mannosylated structures presented in multiple copies on HIV-1 gp120 and promoting virus dissemination. Inhibition of HIV interaction with DC-SIGN thus represents a potential therapeutic approach for viral entry inhibition at the mucosal level. Design:Herein we evaluate the efficacy in inhibiting HIV-1 infection and the potential toxicity of a multimeric glycomimetic DC-SIGN ligand (Dendron 12). Methods:The ability of Dendron 12 to block HIV-1 infection was assessed in cellular and human cervical explant models. Selectivity of Dendron 12 towards DC-SIGN and langerin was evaluated by surface plasmon resonance studies. &bgr; chemokine production following stimulation with Dendron 12 was also analyzed. Toxicity of the compound was evaluated in cellular and tissue models. Results:Dendron 12 averted HIV-1 trans infection of CD4+ T lymphocytes in presence of elevated viral loads and prevented HIV-1 infection of human cervical tissues, under conditions mimicking compromised epithelial integrity, by multiple clades of R5 and X4 tropic viruses. Treatment with Dendron 12 did not interfere with the activity of langerin and also significantly elicited the production of the &bgr; chemokines MIP-1&agr;, MIP-1&bgr; and RANTES. Conclusion:Dendron 12 thus inhibits HIV-1 infection by competition with binding of HIV to DC-SIGN and stimulation of &bgr;-chemokine production. Dendron 12 represents a promising lead compound for the development of anti-HIV topical microbicides.

Nanorods versus nanovesicles from amphiphilic dendrofullerenes.

Three new amphiphilic dendrofullerenes endowed with 4, 8, and 16 carboxylic groups have been efficiently prepared by using a click chemistry methodology. These amphiphilic fullerene derivatives aggregate forming micelles, nanorods, or hollow vesicles depending on the concentration and on the solid substrate.

Targeting DC-SIGN with carbohydrate multivalent systems.

DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin), a C-type lectin mainly present at the surface of immature dendritic cells, plays a relevant role activating and tailoring adaptive immune responses against different pathogens. This lectin recognizes, in a multivalent and calcium-dependent manner, highly glycosylated proteins present at the surface of pathogens. Several groups have devoted remarkable efforts to develop carbohydrate multivalent compounds targeting this lectin to modulate its role in pathogen capture and in the generation of an immune response. Most of these approaches have been based on mannosylation of immunogenic proteins such as ovalbumin but new strategies have been envisaged to achieve these goals. Although mannosylated systems cannot provide the required selectivity for a specific lectin at dendritic cells, fucosylated compounds have overcome this problem specifically targeting DC-SIGN and avoiding interferences with other lectins, such as the mannose receptor. The use of these carbohydrate multivalent compounds to target DC-SIGN can be considered a promising strategy to inhibit pathogen entry and to develop new vaccines against pathogen infection or cancer. New studies are required to provide more insights into the complex immune pathway involving DC-SIGN.