Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds

Ethan A. Englund, Deyun Wang, Hidetsugu Fujigaki, Hiroyasu Sakai, Christopher M. Micklitsch, Rodolfo Ghirlando, Gema Martin-Manso, Michael L. Pendrak, David D. Roberts, Stewart R. Durell and Daniel H. Appella ()
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Ethan A. Englund: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.
Deyun Wang: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.
Hidetsugu Fujigaki: Laboratory of Cell Biology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
Hiroyasu Sakai: Laboratory of Cell Biology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
Christopher M. Micklitsch: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.
Rodolfo Ghirlando: Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.
Gema Martin-Manso: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
Michael L. Pendrak: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
David D. Roberts: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
Stewart R. Durell: Laboratory of Cell Biology, CCR, NCI, NIH, Bethesda, Maryland 20892, USA.
Daniel H. Appella: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.

Nature Communications, 2012, vol. 3, issue 1, 1-7

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1629

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