Cell penetrating peptides (CPPs) are peptides capable of crossing the cellular membrane and transporting cargoes into the cell. In most cases CPPs are cationic peptides, 8-30 amino acids long and commonly either primary or secondary amphipathic.
CPPs have gained considerable interest as potential delivery systems for drugs and oligonucleotide therapies; most of this has been focused on peptides derived from naturally occurring proteins or chimeric combinations of protein-derived and synthetic sequences. Purely synthetic CPPs have also been reported, in many cases synthetic peptides are simple poly-amino acid sequences such as polyarginines, but there are also examples more complex synthetic structures.
In a recent study, we have developed a series of novel cell-penetrating peptides using a combination of the model amphipatic peptide (MAP) sequence and PepFect strategies. Stearyl-MAP and a series of stearyl modified MAP analogues were designed and synthesized. The novel peptides were found to form non-covalent peptide-plasmid complexes by co-incubation of peptides and plasmids in water solution, the complexes were characterized by dynamic light scattering and cellular uptake of the complexes was studied in a luciferase based plasmid transfection assay. A quantitative structure-activity relationship (QSAR) model of cellular uptake was developed and experimental uptake data correlated to QSAR predictions. The predicted biological effects obtained from the model correlated well with experimental data. This QSAR model could potentially be used to understand structural requirements for cell penetration, or to predict novel CPP sequences.