Pyrrolidine-based cationic γ-peptide: a DNA-binding molecule works as a potent anti-gene agent

Pyrrolidine-based cationic peptides showing high stability to enzyme degradation and strong binding affinity towards DNA are widely investigated as tools to interfere in gene expression. Several studies have been focused on γ-peptide analogs with modifications on the peptide backbone in the attempt to overcome solubility, uptake, and aggregation issues. Pyrrolidine-based γ-peptide derivatives having two different modes of backbone conformation show interesting properties in terms of secondary structure and affinity of binding towards nucleic acids. In this paper, we illustrate our results obtained on two cationic 8-mer γ-peptides Gp1 and Gp2 , and how they differ in side-chain spacing along the backbone was tested for DNA binding and DNA transfection activity. Both γ-peptides are stable toward protease digestion. Gp1 binds to DNA more tightly than GP2 . This binding ability of Gp1 is attributed to its characteristic of single-chain PPII-like conformation. The Gp1 shows a reduction in its electrophoretic mobility when treated with plasmid DNA. The DNA transfection ability of γ-peptide Gp1 was compared with commercially available transfection reagent Effectene. In each case, Gp1 significantly enhanced the transfection efficiency (40%) of plasmid in Schneider cells compared to the commercial reagent (18%). The other γ-peptide GP2 is not active.