Programmable multivalent display of receptorligands using peptide nucleic acid nanoscaffolds

摘要

Multivalent effects dictate the binding affinity of multiple ligands on one molecular entity toreceptors. Integrins are receptors that mediate cell attachment through multivalent binding topeptide sequences within the extracellular matrix, and overexpression promotes the metastasisof some cancers. multivalent display of integrin antagonists enhances their efficacy, butcurrent scaffolds have limited ranges and precision for the display of ligands. Here we presentan approach to studying multivalent effects across wide ranges of ligand number, density,and three-dimensional arrangement. using l-lysine γ-substituted peptide nucleic acids, themultivalent effects of an integrin antagonist were examined over a range of 1–45 ligands. Theoptimal construct improves the inhibitory activity of the antagonist by two orders of magnitudeagainst the binding of melanoma cells to the extracellular matrix in both in vitro and in vivomodels.