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Polyvalency
Polyvalency is the simultaneous interaction of multiple ligands with multiple receptors (Figure 1). The objective of our research on this subject is to understand the characteristics of polyvalency in biochemical systems, and to use this understanding to develop new types of drugs, reagents, and procedures for use in medicine and biology.
Much of biochemistry and medicinal chemistry has historically focused on the interaction of individual ligands (or substrates) with the active sites of individual proteins. It is, of course, widely understood that many important interactions in biology involve simultaneous interactions of multiple ligands and multiple receptors. Examples include antibodies interacting with ligands on the surfaces of viruses or virally infected cells, pathogens adhering to target cells, interaction of bacterial toxins with cell surfaces, assembly of the attack complex in complement activation, and the interaction of cell-surface receptors with hormones. If molecular recognition is the most fundamental molecular class of events in the cell, multivalent molecular recognition is the least understood part of this class. Our work in polyvalency is focused on three broad themes described below.
Understanding and Using the Divalency of Antibodies
The first objective of this project is to understand why antibodies are (at minimum) divalent, how this divalency leads to enhanced avidity in binding, and how to use this understanding to manipulate them (Figure 2). The potential outcomes of the research are new methods of purifying antibodies, and optimizing antibodies for other uses. It may also provide improved methods of using antibody-based bioanalytical systems, and new approaches to modulating the activities of antibodies in vivo.
Physics of Polymers Presenting Multiple Ligands
The second major focus of this research is the biophysics of polymers presenting multiple ligands and interacting with surfaces presenting multiple receptors (Figure 3). The emphasis in the work is on understanding the phenomena exhibited by polymeric polyvalency, and on using this understanding to test new concepts in managing bacterial and viral infectious disease.
The Kinetic and Thermodynamic Basis for Polyvalency
The third focus of the work is avidity - the affinity of polyvalent systems of receptors for polyvalent systems of ligands. Avidity in polyvalent systems is widely accepted to reflect some combination of the free energy of binding of individual ligands to individual binding sites, with an entropic advantage that comes with linking the ligands. The interplay of free energy, enthalpy, and entropy in these systems is not well understood. We will combine studies of relationships between structure and affinity in monovalent, divalent, oligovalent, and polyvalent systems with experimental measurements of relevant thermodynamic properties (especially using microcalorimetry), and theory (statistical mechanics and molecular mechanics); the objective of this work is to develop a theory of avidity. A useful theory will help us and others to design successful polyvalent systems, and will provide design rules that will help to apply an important emerging principle: that polyvalent presentation of a ligand, which is itself weakly bound as a monomer, can often lead to very strong biological effects. In this context, polyvalency can be a kind of amplifier of weak biological interactions.
The benefits of the work include: i) improved understanding of the mechanism of binding of antibodies; ii) the potential for modulating this binding, with the possibility for application in research and clinical immunology; iii) development of new approaches to management of infectious disease; iv) more efficient design of targeted ligands and drug leads, by improving understanding of polyvalency (broadly defined); v) new reagents and processes useful in research biochemistry and biology.
Select Publications:
1. Mammen, M., Choi, S. K. and Whitesides, G. M. "Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors"; Angew. Chem., Int. Ed. Eng. 1998, 37, 2755.
2. Choi, S. K., Mammen, M., and Whitesides, G. M. "Generation and in situ evaluation of libraries of poly(acrylic acid) presenting sialosides as side chains as polyvalent inhibitors of influenza-mediated hemagglutination"; J. Am. Chem. Soc. 1997, 119, 4103.
3. Liang, M. N. et al. "Measuring the forces involved in polyvalent adhesion of uropathogenic Escherichia coli to mannose-presenting surfaces"; Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 13092.
4. Metallo, S. J. et al. "Using bifunctional polymers presenting vancomycin and fluorescein groups to direct anti-fluorescein antibodies to self-assembled monolayers presenting D-alanine-D-alanine groups"; J. Am. Chem. Soc. 2003, 125, 4534.
5. Mourez, M. et al. "Designing a polyvalent inhibitor of anthrax toxin"; Nature Biotech. 2001, 19, 958.
6. Qian, X. P. et al. "Arrays of self-assembled monolayers for studying inhibition of bacterial adhesion"; Anal. Chem. 2002, 74, 1805.
7. Qian, X. P. et al. "Measuring the inhibition of adhesion of lectins to the surface of erythrocytes with optically controlled collisions between microspheres and erythrocytes"; J. Phys. Chem. B 2002, 106, 9159.
8. Rao, J. H. and Whitesides, G. M. "Tight binding of a dimeric derivative of vancomycin with dimeric L-Lys-D-Ala-D-Ala"; J. Am. Chem. Soc. 1997, 119, 10286.
9. Rao, J. H. et al. "A trivalent system from vancomycin-D-Ala-D-Ala with higher affinity than avidin-biotin"; Science 1998, 280, 708.
10. Rao, J. H. et al. "Design, synthesis, and characterization of a high-affinity trivalent system derived from vancomycin and L-Lys-D-Ala-D-Ala"; J. Am. Chem. Soc. 2000, 122, 2698.
11. Yang, J. et al. "Self-assembled aggregates of IgGs as templates for the growth of clusters of gold nanoparticles"; Angew. Chem., Int. Ed. Eng. 2004, 43, 1555.
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