Evaluating protein-carbohydrate interactions induced by multivalent carbohydrate-functionalized dendrimers

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Montana State University - Bozeman, College of Letters & Science


Understanding protein-carbohydrate interactions is essential for elucidating biological pathways and cellular mechanisms but is often difficult due to the prevalence of multivalent interactions. A better understanding of the basic behavior of protein-carbohydrate interactions is critical for controlling cellular proliferation and recognition processes for novel therapeutic methods to be successful. Many procedures that exist for evaluating protein-carbohydrate interactions are often limited to monovalent interactions or small polymers. Given that many cellular processes, such as those attributed to the immune system, are enhanced multivalently or are aggregation-driven, there is a need to reveal the behavior and basic requirements for multivalent binding and aggregation. Evaluating these interactions on large, multivalent scaffolds such as synthetically controllable dendrimers provides an important tool towards accurately determining the role of glycosylation in biological systems. Here, different approaches to measure the interactions of proteins with glycodendrimers are described, ranging from simple qualitative assays to novel quantitative methods of assessment. Quantitative methods such as Isothermal Titration Calorimetry and Surface Plasmon Resonance are severely limited when used with multivalent systems, and do not provide as accurate results as monovalent systems. When dealing with multivalent systems, inhibition assays often provide more reproducible results. Through these experiments, it has become increasingly apparent that aggregates play a significant role in multivalent systems, and current methods to evaluate these interactions leave much room for improvement. Assay design is important both for basic identification and understanding of any interaction, especially higher-order interactions involving multivalency. Endgroup patterning and presentation was explored to determine their role in multivalent affinity enhancements. Using a novel fluorescence lifetime method, glycodendrimer-mediated aggregation was successfully characterized. The work here evaluates the effectiveness of assays used for carbohydrate interaction, translated to a multivalent scaffold, with special consideration to large-order aggregates.




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