Many cytokines and other protein ligands have potential for therapeutic use that would be greatly enhanced if the affinity of the ligands for their receptors could be increased significantly. Experimental results and theoretical calculations indicate the affinity of monomeric ligands could be increased 100-1000 fold if the ligand is incorporated into a multivalent construct that permits simultaneous binding of 2 or more receptors on the same cell. The objective of this research project is to create multi-valent ligands for cell surface receptors and determine how structural constraints and changes in valency effect binding avidity, receptor activation, and inhibition of virus infection. This research is expected to provide knowledge and insight to facilitate production of clinically useful high affinity ligands. The model monovalent ligand for this project will be human stromal cell- derived factor-1 (SDF-1). SDF-1 is a ligand for the HIV co-factor receptor CXCR-4. Therefore, in addition to activation CXCR-4 signal transduction, SDF-1 will be high avidity ligands for CXCR-capable of inhibiting HIV infection. Ultimately, it is hoped that SDF-1 multimers, and similar multimeric ligands, will be clinically useful molecules for a variety of disease conditions.
