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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030367-27
Application #
7825264
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
1982-04-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
27
Fiscal Year
2010
Total Cost
$386,694
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Mack, Eric T; Snyder, Phillip W; Perez-Castillejos, Raquel et al. (2012) Dependence of avidity on linker length for a bivalent ligand-bivalent receptor model system. J Am Chem Soc 134:333-45
Mirica, Katherine A; Lockett, Matthew R; Snyder, Phillip W et al. (2012) Selective precipitation and purification of monovalent proteins using oligovalent ligands and ammonium sulfate. Bioconjug Chem 23:293-9
Mecinovic, Jasmin; Snyder, Phillip W; Mirica, Katherine A et al. (2011) Fluoroalkyl and alkyl chains have similar hydrophobicities in binding to the ""hydrophobic wall"" of carbonic anhydrase. J Am Chem Soc 133:14017-26
Snyder, Phillip W; Mecinovic, Jasmin; Moustakas, Demetri T et al. (2011) Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc Natl Acad Sci U S A 108:17889-94
Mack, Eric T; Snyder, Phillip W; Perez-Castillejos, Raquel et al. (2011) Using covalent dimers of human carbonic anhydrase II to model bivalency in immunoglobulins. J Am Chem Soc 133:11701-15
Bilgi├žer, Ba?ar; Thomas 3rd, Samuel W; Shaw, Bryan F et al. (2009) A non-chromatographic method for the purification of a bivalently active monoclonal IgG antibody from biological fluids. J Am Chem Soc 131:9361-7
Krishnamurthy, Vijay M; Kaufman, George K; Urbach, Adam R et al. (2008) Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Chem Rev 108:946-1051
Mack, Eric T; Perez-Castillejos, Raquel; Suo, Zhigang et al. (2008) Exact analysis of ligand-induced dimerization of monomeric receptors. Anal Chem 80:5550-5
Bilgicer, Basar; Moustakas, Demetri T; Whitesides, George M (2007) A synthetic trivalent hapten that aggregates anti-2,4-DNP IgG into bicyclic trimers. J Am Chem Soc 129:3722-8
Krishnamurthy, Vijay M; Semetey, Vincent; Bracher, Paul J et al. (2007) Dependence of effective molarity on linker length for an intramolecular protein-ligand system. J Am Chem Soc 129:1312-20

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