This research will develop multivalency as a strategy for modulating biological interactions. Multivalent interactions are those that involve multiple receptors interacting simultaneously with multiple ligands. Multivalent interactions are ubiquitous in biology-in infectious disease, in processes involving antibodies, in blood clotting, metathesis, platelet activation, and inflammation, and in many conditions in which cells interact with surfaces-but are seldom explicitly the target of study or of therapy. Drugs are designed primarily on the principle of """"""""one drug, one receptor"""""""". The objective of this research is to explore a range of multivalent interactions using multivalent ligands as probes, to understand those types of biologically relevant interactions that are most easily controlled by synthetic, multivalent entities, and to demonstrate proof-of-concept in the use of multivalent species as drugs. Test systems will be drawn primarily from infectious disease: E. coli, pseudomonas, B. anthracis, and influenza are of particular interest. It will also develop new analytical systems that are tailored to the special requirements of multivalency.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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Harvard University
Schools of Arts and Sciences
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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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