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Multivalent Carbohydrate-Protein Interactions Through Self-Assembly

Two of the central building blocks of life are proteins and carbohydrates. The interactions between these two disparate types of biomolecules play a role in numerous biological processes and are critical to the onset, detection, and, potentially, prevention,of human diseases such as cancer. Despite the importance of  these interactions, the binding between an individual protein and an individual carbohydrate is typically quite weak and not very specific. Nature obtains strong and specific responses through multiple protein-carbohydrate interactions, a phenomenon known as multivalency.

Previously, the Baum group (Pathology) have focused on understanding natural multivalent carbohydrateprotein interactions and their biological consequences, particularly in the human immune system, and the Stoddart group (Chemistry and Biochemistry) has focused on developing novel architectures for displaying carbohydrates and multivalency in unnatural systems. Under the aegis of the CNSI, we have initiated an interdisciplinary collaboration to study multivalent protein-carbohydrate interactions using self-assembly and nanotechnology. A potential clue to the understanding of multivalent carbohydrate-protein interactions is that they typically take place at cell surfaces, where one or both of the components are attached to cellular membranes. These are fluid and dynamic interfaces, which suggests that properties such as flexibility and adaptability may play important roles in these multivalent interactions.

Using self-assembly, we have developed highly flexible and adaptable systems (Box) for displaying carbohydrates (lactosides). In the so-called pseudopolyrotaxanes comprised of lactoside-displaying cyclodextrin (CD) “beads” threaded onto linear polyviologen “strings”, the CDs are able to spin around the axis of the polymer chain as well as to move back and forth along its backbone to alter the presentation of lactosides (J. Am. Chem. Soc. 2004, 126, 11914–11922).

We have tested the interactions of these self-assembled, multivalent, nanometer-scale assemblies with galectin-1, a dimeric lactoside-binding protein with two binding sites. Galectin-1 plays a prominent role in the immune system and in certain human cancers. Synthetic multivalent ligands for galectin-1 have potential as cancer diagnostics and therapeutics. The self-assembled pseudopolyrotaxanes outperformed a more traditional polymer with covalently attached lactosides in Tcell agglutination assays, with valency-corrected enhancements of up to 10-fold over native lactose. The flexible and dynamic ligand presentation by pseudopolyrotaxanes adds a new dimension to the study of protein-carbohydrate interactions and the exploitation of multivalency for targeting therapeutically relevant lectins.

 

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