Multivalency is the simultaneous interaction of multiple ligands with multiple receptors. It is a type of interaction that is ubiquitous in biology and biomedicine. This research program will understand and exploit the characteristics of multivalency to control the strength of binding (the """"""""avidity"""""""") in multivalent biochemical systems. It has three broad themes: i) Understanding and using the divalency of antibodies, ii) Understanding the biophysical basis (kinetic, thermodynamic, and theoretical) for multivalency, iii) Understanding the interaction of polymers presenting multiple copies of systems for molecular recognition to the surfaces of viruses and bacteria. The project has seven technical foci. It will: i) Examine the relations between the structures of di- and trivalent ligands and the structures of aggregates they form with antibodies, and use these systems as a test bed to examine relations between structures, binding constants, and avidities, ii) Examine the influence of groups (""""""""linkers"""""""") used in synthetic di- and trivalent ligands on the avidity of these ligands for antibodies and antibody mimics, iii) Develop new methods for purification and analysis of antibodies based on the formation of cyclic aggregates with oligovalent ligands, iv) Explore """"""""antibody mimics""""""""-covalently linked dimers of carbonic anhydrase-that show some of the properties of antibodies in multivalent binding, v) Develop strategies for enhancing the binding of small, monovalent ligands to proteins by adding molecular surface to the ligand capable of binding to the surface of the adjacent binding site-a loose extension of the concept of divalency, vi) Develop polymeric, polyvalent ligands, and examine their interaction with surfaces of cells and viruses, vii) Develop theory to help to rationalize and predict oligovalency and avidity. 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 receptor-targeted ligands and drug leads;v) new reagents and processes useful in biochemistry and biology research.
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