Research Projects
Using dendrimers to study multivalent protein-carbohydrate interactions.
Figure 1
Figure 2
Figure 3
We are using dendrimers (macromolecules consisting of a series of branches around an inner core) to study the interaction of carbohydrates with receptor proteins called lectins. Although a wide variety of biological processes including fertilization, development, and the mounting of an immune response rely on protein-carbohydrate interactions for cellular recognition and adhesion (Figure 1), these interactions are not well understood. Because the affinity of lectins for individual saccharide units is relatively weak, the adhesion of lectins to saccharides on the surface of a cell involves multipoint attachment (multivalency).
We are using saccharide-functionalized poly(amidoamine) (PAMAM) dendrimers (Figure 2) to learn more about multivalency in protein carbohydrate interactions. Dendrimers are ideal frameworks for the study of how systematic structural changes alter the way that a glycopolymer interacts with a protein. In addition to changing the dendrimer generation, the degree of carbohydrate loading on a dendrimer can also be readily changed by controlling the number of equivalents of sugar residues that are added to the dendrimer (Figure 3). We can systematically and predictably attenuate the relative affinities of the dendrimers for the lectins by incorporating low and high affinity ligands into the dendrimer. We can also influence how many proteins bind to each dendrimer. We're evaluating the comparative activity of these dendrimers for lectins such as Concanavalin A, Pisum Sativum, and Cyanovirin N using a variety of assays. In this way, we are learning about the factors that control physiologically relevant multivalent protein-carbohydrate interactions. Because of their ready tunability, the carbohydrate functionalized dendrimers described here should provide guidelines for the development of synthetic multivalent frameworks for many applications in chemical biology.
Publications
Samuelson, L. E., Sebby, K. B., Walter, E. D., et al., "EPR and affinity studies of mannose-TEMPO functionalized PAMAM dendrimers." Organic and Biomolecular Chemistry 2 (21) 3075, 2004.
Woller EK, Cloninger MJ
, "The Lectin-binding Properties of Six Generations of Mannose-functionalized Dendrimerss
." Org. Lett. 4 7-10 (2002)
Woller EK, Cloninger MJ
, "Mannose Functionalization of a Sixth Generation Dendrimer
." Biomacromolecules 2 1052-1054 (2001)
Mangold, S. L.; Cloninger, M. J. , "Binding of monomeric and dimeric Concanavalin A to mannose functionalized dendrimers." Org. Biomol. Chem. 2006, 4, 2458-2465.
Wolfenden, M. L.; Cloninger, M. J. , "Mannose/glucose-functionalized dendrimers to investigate the predictable tunability of multivalent interactions.." J. Am. Chem. Soc., 2005, 127, 12168-12169
Schlick, K. H.; Udelhoven, R. A.; Strohmeyer, G. C.; Cloninger, M. J. , "Binding of Mannose-Functionalized Dendrimers with Pea (Pisum Sativum) Lectin." Mol. Pharm. 2005, 2, 295-301
Mangold, S. L.; Morgan, J. R.; Strohmeyer, G. C.; Gronenborn, A. M.; Cloninger, M. J., "Cyanovirin-N binding to Mana1-2Man functionalized dendrimers." Org. Biomol. Chem., 2005, 3, 2354-2358
Woller EK, Walter ED, Morgan JR, Singel DJ, Cloninger MJ
, "Altering the Strength of Lectin Binding Interactions and Controlling the Amount of Lectin Clustering Using Mannose/hydroxyl Functionalized Dendrimers
." J. Am. Chem. Soc. 125 8820–8826 (2003)
Personnel:
Mary Cloninger
Keywords:
Biochemistry, Chemical Biology, Organic
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