A general glycomimetic scaffold yields probes to explore C-type lectin function

Carbohydrate---protein interactions are essential for numerous cellular processes, but their study has been hindered by a lack of suitable probes. I sought to address this deficiency by devising a privileged scaffold that could be adapted to identify inhibitors of one class of carbohydrate-binding proteins (lectins), the C-type lectins. C-type lectins are a large class of proteins that are integral to immune system function. I showed the natural product shikimic acid could be transformed into a privileged scaffold, to yield glycomimetic structures that bind to the mannose-binding C-type lectin DC-SIGN. My results highlight the generality of this approach. Specifically, I identified inhibitors that are better ligands than the natural monosaccharides that bind DC-SIGN. Moreover, my compounds exhibit selectivity for DC-SIGN over a closely related C-type lectin, mannose-binding protein A.;The shikimic acid-based scaffold makes an effective mannose mimic. To expand this strategy to a broader range of lectins, however, the capability to mimic a variety of carbohydrate epitopes recognized by lectins is needed. In theory, mimics of any of the basic carbohydrates recognized by lectins could be accessed using different diastereomers of shikimic acid as scaffolds. To this end, one epimer of shikimic acid, (--)-4-epi-shikimic acid, has been used to produce glycomimetics that could be used to target DC-SIGN selectively over a related protein, DC-SIGNR, on the basis of known binding differences. Unlike shikimic acid, this epimer is not commercially available. Consequently, I have designed and completed a novel synthetic route to access this compound, and studies to explore its use as a glycomimetic scaffold are ongoing.;In nature, carbohydrate---lectin interactions utilize multivalency to achieve the potency necessary to mediate biological processes. Accordingly, I hypothesized that multivalency could be exploited to improve the potency of the glycomimetic compound. Multivalent displays of the shikimic acid-based glycomimetic represent some of the most potent inhibitors of DC-SIGN yet indentified. Additionally, these compounds produce many of the same biological effects as the natural ligands. Studies on the use of these multivalent ligands to explore the function of DC-SIGN are ongoing.