Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds
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Published on: July 25, 2022
Ethan A Englund1, Deyun Wang, Hidetsugu Fujigaki
1Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland 20892, USA.
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.
Insights
Researchers explored multivalent binding effects using peptide nucleic acids to optimize integrin antagonists. This approach significantly enhanced the antagonist
Area of Science:
- Biochemistry and Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Multivalent effects, where multiple ligands bind to receptors, are crucial for molecular interactions.
- Integrins are key cell receptors involved in cell adhesion and cancer metastasis.
- Current methods for multivalent ligand display have limitations in range and precision.
Purpose of the Study:
- To develop a novel approach for studying multivalent effects across a wide range of ligand numbers, densities, and 3D arrangements.
- To investigate the impact of multivalent display on the efficacy of integrin antagonists.
Main Methods:
- Utilized L-lysine γ-substituted peptide nucleic acids as scaffolds for multivalent ligand display.
- Examined the multivalent effects of an integrin antagonist with varying numbers of ligands (1-45).
- Evaluated the inhibitory activity against melanoma cell binding to the extracellular matrix in vitro and in vivo.
Main Results:
- Identified an optimal construct for multivalent display of the integrin antagonist.
- Demonstrated a two-orders-of-magnitude improvement in inhibitory activity with the optimized construct.
- Validated the enhanced efficacy in both in vitro and in vivo models of melanoma cell adhesion.
Conclusions:
- The developed scaffold enables precise control over multivalent ligand display for studying molecular interactions.
- Optimized multivalent integrin antagonists show significantly enhanced efficacy in inhibiting cancer cell metastasis.
- This approach offers a promising strategy for developing more effective cancer therapeutics.
