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; Daniel H. Appella

doi:10.1038/ncomms1629

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, Daniel H. Appella

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

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	https://doi.org/10.1038/ncomms1629
Publication status	Published - 2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms1629

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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.",

author = "Englund, {Ethan A.} and Deyun Wang and Hidetsugu Fujigaki and Hiroyasu Sakai and Micklitsch, {Christopher M.} and Rodolfo Ghirlando and Gema Martin-Manso and Pendrak, {Michael L.} and Roberts, {David D.} and Durell, {Stewart R.} and Appella, {Daniel H.}",

year = "2012",

doi = "10.1038/ncomms1629",

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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, 2012.

Research output: Contribution to journal › Article › peer-review

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AU - Englund, Ethan A.

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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.

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Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds

Abstract

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