Plasmid DNA Delivery Using Cell-Penetrating Peptide Foldamers Composed of Arg–Arg–Aib Repeating Sequences

Abstract

Arginine (Arg)-rich cell-penetrating peptides (CPPs) are promising tools for plasmid DNA (pDNA) delivery. α-Aminoisobutyric acid (Aib) is known to stabilize peptide helical secondary structures and has been used as a building block for foldamers. In the current study, we prepared Aib CPP foldamers, (Arg–Arg–Aib) n (n = 1–6) and examined their pDNA transfection abilities. Transfection efficiencies of peptide/pDNA complexes are dependent on peptide chain length, with longer peptides (n ≥ 4) exhibiting better transfection abilities than an Arg nonapeptide. Furthermore, Aib CPP foldamers achieve prolonged transfection abilities compared with commercially available transfection reagents, which is probably because of the high resistance of the peptides to enzymatic degradation, thereby protecting the encapsulated pDNA for a long period. The obtained results demonstrated promising features of Aib CPP foldamers as pDNA delivery carriers.

Introducing the Chiral Constrained α‐Trifluoromethylalanine in Aib Foldamers to Control, Quantify and Assign the Helical Screw‐Sense**

“…In particular, the field of peptide‐based foldamers has gained considerable interest in medicinal chemistry to circumvent some of the issues of short peptides by increasing their conformational stability and their stability towards proteolysis [3,4] . This feature makes peptidomimetic foldamer chemistry an important resource for the design of cell penetrating peptides (CPP), [5–9] antimicrobial peptides (AMP) [10–12] and inhibitors of protein‐protein interactions (PPI) [13,14] …”

“…[1,2] In particular, the field of peptide-based foldamers has gained considerable interest in medicinal chemistry to circumvent some of the issues of short peptides by increasing their conformational stability and their stability towards proteolysis. [3,4] This feature makes peptidomimetic foldamer chemistry an important resource for the design of cell penetrating peptides (CPP), [5][6][7][8][9] antimicrobial peptides (AMP) [10][11][12] and inhibitors of protein-protein interactions (PPI). [13,14] Among the different types of foldamers, those constituted by several units of α-aminoisobutyric acid (Aib) have been widely investigated for their ability to form stable 3 10 -helices [15,16] and their similitude with peptaibols, a natural type of AMP.…”

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

“…dAAs can stabilize the secondary structures of oligopeptides, and α-methylated and cyclic dAAs are often used [32][33][34][35][36][37][38]. dAAs are incorporated into functionalized helix-stabilized peptides such as organocatalysts [38][39][40], drug delivery system (DDS) carriers [41][42][43][44][45][46], and antimicrobials [47][48][49][50]; however, there are only a few examples of their use as PPI inhibitors. Reported PPI inhibitors containing dAAs are listed in Table 1.…”

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

“…Cell‐penetrating peptides (CPPs) are a broad group of short peptides that translocate across cell membranes and can make non‐covalent complexes with double‐stranded nucleic acids driven by ionic interactions. CPPs can be used to deliver potentially therapeutic molecules, including DNA, [ 223 ] siRNA, [ 224 ] and also miRNA. [ 225 ]…”