We have designed a glycodendritic structure, BH30sucMan, that blocks the interaction between dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and Ebola virus (EBOV) envelope. BH30sucMan inhibits DC-SIGN-mediated EBOV infection at nanomolar concentrations. BH30sucMan may counteract important steps of the infective process of EBOV and, potentially, of microorganisms shown to exploit DC-SIGN for cell entry and infection.
Multivalent scaffolds bearing carbohydrates have been prepared to mediate biological processes where carbohydrates are involved. These systems consist of dendritic structures based on Boltorn H20 and H30 hyperbranched polymers to which carbohydrates are linked through a convenient spacer. Mannose has been chosen as a sugar unit to test the viability of this strategy. These glycodendritic compounds have been prepared in a few steps with good yields, showing a high solubility in physiological media and low toxicity. The binding of these dendritic polymers to the mannose-binding lectin Lens culinaris (LCA) was studied using STD-NMR experiments and quantitative precipitation assays. The results demonstrate the existence of a clear interaction between the mannose derivative systems and the Lens lectin where the dendritic scaffold does not have an important role in mannose binding but supplies the necessary multivalence for lectin cluster formation. These glycodendritic structures are able to interact with a receptor, and therefore they can be considered as promising tools for biological studies.
Human CD1c is a protein that activates alphabeta T cells by presenting self antigens, synthetic mannosyl phosphodolichols, and mycobacterial mannosyl phosphopolyketides. To determine which molecular features of antigen structure confer a T cell response, we measured activation by structurally divergent Mycobacterium tuberculosis mannosyl-beta1-phosphomycoketides and synthetic analogs with either stereorandom or stereospecific methyl branching patterns. T cell responses required both a phosphate and a beta-linked mannose unit, and they showed preference for C(30-34) lipid units with methyl branches in the S-configuration. Thus, T cell responses were strongest for synthetic compounds that mimicked the natural branched lipids produced by mycobacterial polyketide synthase 12. Incorporation of methylmalonate to form branched lipids is a common bacterial lipid-synthesis pathway that is absent in vertebrates. Therefore, the preferential recognition of branched lipids may represent a new lipid-based pathogen-associated molecular pattern.
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