Structure-based peptide ligand design for improved epidermal growth factor receptor targeted gene delivery

Simon Decker; Alexander Taschauer; Emanuela Geppl; Viktoria Pirhofer; Michael Schauer; Stephan Pöschl; Florian Kopp; Lars Richter; Gerhard F. Ecker; Haider Sami; Manfred Ogris

doi:10.1016/j.ejpb.2022.05.004

Titel

Structure-based peptide ligand design for improved epidermal growth factor receptor targeted gene delivery

Autor*in

Simon Decker

Department für Pharmazeutische Wissenschaften, Fakultät für Lebenswissenschaften, Universität Wien

Alexander Taschauer

Department für Pharmazeutische Wissenschaften, Fakultät für Lebenswissenschaften, Universität Wien

Emanuela Geppl

Department für Pharmazeutische Wissenschaften, Fakultät für Lebenswissenschaften, Universität Wien

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Abstract

The epidermal growth factor receptor EGFR allows targeted delivery of macromolecular drugs to tumors. Its ligand, epidermal growth factor, binds EGFR with high affinity but acts mitogenic. Non-mitogenic peptides are utilized as targeting ligands, like the dodecapeptide GE11, although its low binding affinity warrants improvement. We applied a two-step computational approach with database search and molecular docking to design GE11 variants with improved binding. Synthesized peptides underwent binding studies on immobilized EGFR using surface plasmon resonance. Conjugates of peptides coupled via heterobifunctional PEG linker to linear polyethylenimine (LPEI) were used for transfection studies on EGFR-overexpressing cells using reporter gene encoding plasmid DNA. Docking studies unraveled similarities between GE11 and the EGFR dimerization arm. By skipping non-overlapping amino acids, a less hydrophobic segment (YTPQNVI) was identified to be directly involved in EGFR binding. By replacing valine by tyrosine, a full-length version with proposed enhanced binding (GE11m3) was developed. While hydrophobic or hydrophilic segments and variations thereof exhibited low binding, GE11m3 exhibited 3-fold increase in binding compared to GE11, validating in silico predictions. In transfection studies, polyplexes with GE11m3 induced a significantly higher reporter gene expression when compared to GE11 polyplexes both on murine and human cancer cells overexpressing EGFR.

Stichwort

PolyplexTransfectionTargeted gene deliveryEGFRGE11

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

https://phaidra.univie.ac.at/o:1637981

DOI

10.1016/j.ejpb.2022.05.004

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