title: Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds.
abstract: Multivalent effects dictate the binding affinity of multiple ligands on one molecular entity to receptors. Integrins are receptors that mediate cell attachment through multivalent binding to peptide sequences within the extracellular matrix, and overexpression promotes the metastasis of some cancers. Multivalent display of integrin antagonists enhances their efficacy, but current scaffolds have limited ranges and precision for the display of ligands. Here we present an approach to studying multivalent effects across wide ranges of ligand number, density, and three-dimensional arrangement. Using L-lysine γ-substituted peptide nucleic acids, the multivalent effects of an integrin antagonist were examined over a range of 1-45 ligands. The optimal construct improves the inhibitory activity of the antagonist by two orders of magnitude against the binding of melanoma cells to the extracellular matrix in both in vitro and in vivo models.
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Englund
authors.forename: Deyun
authors.initials: D
authors.lastname: Wang
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Fujigaki
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Micklitsch
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Ghirlando
authors.forename: Gema
authors.initials: G
authors.lastname: Martin-Manso
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.forename: Stewart R
authors.initials: SR
authors.lastname: Durell
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Appella
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D020128:Inhibitory Concentration 50; D016023:Integrins / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D008546:Melanoma, Experimental; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D020135:Peptide Nucleic Acids / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D016023:Integrins; D008024:Ligands; D020135:Peptide Nucleic Acids; D004247:DNA