Considering the importance of protein-carbohydrate interactions in biological processes, effective interference with these interactions may prove to be a powerful way towards novel therapeutics. Multivalency is an important principle that characterizes these interactions and is likely a required design principle for the synthesis of molecules with the goal to interfere effectively. Glycodendrimer synthesis is described here along with interference with animal, plant and bacterial lectins. Large affinity enhancements due to multivalency were observed in selected cases. Initial studies with peptide sequences as interfering moieties in protein carbohydrate interactions are also described which yield ligands in the milimolar range
Galectins have been shown to have a variety of activities associated with binding to extracellular glycoconjugates present on the cell surfaces and extracellular matrices. However, many galectins are detected inside the cells in locations, such as nucleus and phagosomes, suggestive of intracellular functions. In some cases, their translocation from one cellular compartment to another has been demonstrated. Specific functions consistent with intracellular localization have now been documented for some galectins. Galectin-1 and -3 have been identified as pre-mRNA splicing factors. Galectin-3, -7, and -12 have been shown to regulate apoptosis, being either anti-apoptotic or pro-apoptotic. Galectin-3 and -12 have been shown to regulate the cell cycle. The multifunctionality of these galectins is probably related to their ability to interact with multiple proteins. Indeed, a number of intracellular proteins have been identified to interact with galectins, in a manner that is dependent on protein-protein in-teractions, rather than lectin-carbohydrate interactions. However, their roles in the observed functions of galectins have not yet been established. Galectins have also been shown to recognize intracellular proteins through binding to their saccharide side chains. Future studies may reveal binding of galectins to glycoconjugates on internalized particles including those associated with intracellular microorganisms.
The innate immune system provides the first line of defence against infection and is crucial for inducing protection. Invading pathogens are recognized by pathogen-recognition receptors, including Toll-like receptors and C-type lectins (CLRs) expressed on the cell-surface of dendritic cells (DCs). Once a DC has captured pathogen-derived antigens, it undergoes considerable changes that are focussed on elimination of the pathogen. CLRs specifically capture carbohydrate antigens present on the surface or secreted products of pathogens, resulting in antigen processing and presentation. Current data, however, suggest that CLRs have a dual function: in addition to recognition of pathogen-derived antigens, they also function as recognition elements for glycosylated self-antigens to induce homeostatic control and tolerance. Interestingly, pathogens have evolved strategies to suppress or modulate the host immune response by exploiting these CLR functions. For example, Mycobacterium tuberculosis secretes glycosylated antigens that target host CLRs resulting in immune suppression, and several pathogenic nematodes secrete CLRs that may compete with host CLRs for binding to their ligands and may so modulate immune function. A better understanding of the molecular basis of CLR-carbohydrate interactions in infections, and their functional effects on innate immunity is pivotal to develop strategies to fight infectious disease.
Rhizobium bacteria interact with leguminous plants to form symbiotic nitrogen-fixing root nodules. Rhizobia present a mosaic of surface polysaccharides, each of which specifically involved in plant root colonisation, attachment and infection. This review describes the situation for R. leguminosarum biovar viciae, a symbiote of pea and vetch, for which seven surface polysaccharides have now been characterized. Special attention is given to interactions with specific legume lectins at the root surface, in relation to host-plant-specificity of the root nodule symbiosis.