1 Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Isla de la Cartuja, Americo Vespucio s/n, Sevilla 41092; 2 Laboratorio de Microbiología Molecular, Servicio de Microbiología, Hospital Universitario 12 de Octubre, Madrid, Spain
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Abstract |
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Keywords: Boltorn , DC-SIGN , dendrimers , Ebola virus
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Dendritic molecules: multivalent scaffolds with biological applications |
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One of the most attractive applications in the biomedical field is the use of functionalized dendrimers as antiviral agents. These dendrimers are able to form stable complexes with viral structures or receptors at the cell surface, resulting in disruption of the viruscell interaction during the infection process.
Among the few examples found in the literature, we would like to highlight the dendrimers based on the polyamidoamine (PAMAM) support. These PAMAM scaffolds have been functionalized with negatively charged molecules to generate polyanion structures able to interact with viral envelope glycoproteins, thus preventing the binding of viruses such as human immunodeficiency virus (HIV) or herpes simplex virus (HSV) to the surface of target cells.47 These antiviral dendrimers have been tested in vitro for HIV4 and HSV6 and in vivo for HSV in mice5 and guinea pig7 models and can be considered as promising candidates as microbicides after adequate formulation.
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Glycodendrimers |
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Carbohydrates confer to these systems high selectivity to interact with specific lectin receptors; however, until recently, few glycodendrimers have found biomedical applications. For instance, one of these applications enables these molecules to interact with Fimbrae protein to avoid infection by Escherichia coli.9 Another interesting example is a fourth-generation PAMAM dendrimer conjugated with sialic acid.10,11 These sialic acids present at the dendrimer surface are able to interact with haemagglutinin, the major surface glycoprotein of influenza A virus, and prevent viral adhesion to target cells exhibiting sialic acid at their surfaces. This activity has been tested in vitro and in vivo using a murine influenza pneumonitis model.11 To the best of our knowledge, this is the only example described of glycodendrimers as antiviral drugs.
In this way, the main antiviral strategy so far has been based on the binding of the dendrimer to the viral surface. However, many viruses, such as influenza A virus or HIV, present a high degree of mutation leading to major changes in the envelope protein glycosylation patterns when comparing the different strains. This is one of the reasons why the development of a viral vaccine is so elusive in these particular cases. It is worth noting that in the in vivo study by Landers et al.11 on influenza, the sialic acid-glycodendrimer was able to inhibit some but not all influenza strains depending on the haemagglutinin type. Interestingly, the in vitro haemagglutination inhibition assay was highly predictive of in vivo results, highlighting the importance of excellent cell culture models for drug design. A different, although complementary, approach to designing antiviral drugs could be based on targeting the receptor for viral docking at the cell surface to disrupt the ability of the virus to bind specific cells, and the process of membrane fusion and penetration. This aim requires an exhaustive knowledge of the virushost interaction at the cellular and molecular level.
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DC-SIGN as pathogen receptor |
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The key process during this interaction is the multivalent, calcium-dependent recognition by the CRD of DC-SIGN of specific high mannose oligosaccharides structures found characteristically at the surface of certain pathogens. Although it is clear that DC-SIGN has an original pathogen-recognition role, it is also plausible that this molecule is used by certain agents for important steps in the infective process, as has been demonstrated for HIV and Ebola virus.16 These features make DC-SIGN an important target for the design of new drugs. These drugs have to act as anti-adhesive moleculesblocking the binding between the pathogen glycoproteins and DC-SIGN. Owing to the low affinity of carbohydrateprotein interactions, these drugs should have a multivalent presentation of the corresponding carbohydrate epitopes.
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Hyperbranched dendritic polymers: promising new antiviral drugs |
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These preliminary results support the potential application of these systems as antiviral compounds. Research to address the bioavailability and stability of Boltorn-based glycodendrimers is currently in progress. In case these glycodendritic structures are recognized and degraded by mannosyl glycosylases, we have envisaged as a strategy the use of mimic carbohydrates that interact with a receptor but that are not recognized by hydrolytic enzymes.
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Outlook |
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Acknowledgements |
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Footnotes |
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References |
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