Intracellular delivery of biologically active multivalent ligands

AEI 22

Erin E. McElroy, mcelroy@chem.wisc.edu, Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706 and Laura L. Kiessling, Departments of Chemistry and Biochemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706.
Many biological systems rely on multivalent binding for selectivity and activity. Our research group and others have studied multivalent interactions at the cell surface; however, the exploration of multivalent interactions within the cell is extremely challenging. The major barrier is the development of a method for internalization of a synthetic multivalent display. To address this problem, we have used the ring-opening metathesis polymerization to synthesize a block copolymer that can be internalized by cells. The block copolymer design is general; consequently, we have used it to generate multivalent ligands targeting microtubules, an essential component of the cytoskeleton. Derivatives of known inhibitors of microtubule dynamics were synthesized and conjugated to the polymeric scaffold. We demonstrated the internalization ability and biological activity of the compounds. Thus, our system can be used to study and promote protein assemblies within the cell.