General Overview of the Cloninger Research Program

Mary Cloninger

The overarching goal of this research program is to develop synthetic multivalent frameworks for the discernment and manipulation of biological recognition processes that are important in intercellular interactions. Multivalency, which occurs when two or more molecular recognition events take place simultaneously between two entities, plays a critical role in many biological interactions. Diseases in which multivalent interactions have an important role include AIDS, hepatitis, influenza, methicillin-resistant Staphylococcus aureus, tuberculosis, Streptococcus, Staphylococcus, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, diabetes, and cancer. Because typical individual receptor/ligand interactions in biology are often weak, augmentation of these interactions using multivalency can enhance functional avidity. Moreover, multivalent interactions can create matrices that can be used to modulate processes in novel ways, and these architectures of aggregated structure cannot be formed by traditional small-molecule therapeutics.

Dendrimers are highly branched macromolecular compounds. We use dendrimers as multivalent scaffolds on which to append ligands. Higher generation dendrimers are three-dimensionally (relatively) well-defined compounds in the nanometer size regime and as such are ideal probes for multivalent biological recognition events. The size of the dendrimer can be varied by changing the generation of dendrimer that is used. In addition, we have developed techniques for dendrimer functionalization that allow us to vary the loading distribution of dendrimer endgroups.

Multivalent protein-carbohydrate interactions are the focus of much of our research using dendrimers. Protein-carbohydrate interactions on the cell surface have been implicated in a wide variety of intercellular recognition processes such as for the recruitment and activation of cells for mechanisms of inflammation and for the mounting of an immune response, for the infection of host cells by viruses and bacteria, for the adhesion and metastatic spread of cancer cells, and even for cellular differentiation and growth (Figure 1).

figure 1

Figure 1.: A schematic of multivalent protein-carbohydrate interactions at the cell surface.