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.
| Original language | English |
|---|---|
| Article number | 614 |
| Journal | Nature Communications |
| Volume | 3 |
| DOIs | |
| Publication status | Published - 13-02-2012 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
}
Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds. / Englund, Ethan A.; Wang, Deyun; Fujigaki, Hidetsugu; Sakai, Hiroyasu; Micklitsch, Christopher M.; Ghirlando, Rodolfo; Martin-Manso, Gema; Pendrak, Michael L.; Roberts, David D.; Durell, Stewart R.; Appella, Daniel H.
In: Nature Communications, Vol. 3, 614, 13.02.2012.Research output: Contribution to journal › Article
TY - JOUR
T1 - Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds
AU - Englund, Ethan A.
AU - Wang, Deyun
AU - Fujigaki, Hidetsugu
AU - Sakai, Hiroyasu
AU - Micklitsch, Christopher M.
AU - Ghirlando, Rodolfo
AU - Martin-Manso, Gema
AU - Pendrak, Michael L.
AU - Roberts, David D.
AU - Durell, Stewart R.
AU - Appella, Daniel H.
PY - 2012/2/13
Y1 - 2012/2/13
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms1629
DO - 10.1038/ncomms1629
M3 - Article
VL - 3
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 614
ER -