Background

Delivery systems, including peptide-based ones, that destabilize endosomes in a pH-dependent manner are increasingly used to deliver cargoes of therapeutic interest such as nucleic acids and proteins into mammalian cells.

Methods

The negatively charged amphipathic alpha-helicoidal forming peptide named HELP is a derivative from the bee venom melittin and was shown to have a pH-dependent activity with the highest lytic activity at pH 5.0 while becoming inactive when the pH is increased. In the present work, we asked whether replacement in the HELP peptide of the glutamic acid residues by histidines - whose protonation state is sensitive to the pH changes that occur during endosomal acidification - can transform this fusogenic peptide into a carrier able to deliver different nucleic acids into mammalian cells.

Results

Our results show that the resulting HELP-4H peptide displays high plasmid DNA, siRNA and mRNA delivery capabilities. Importantly, in contrast to other cationic peptides its transfection activity was only marginally affected by the presence of serum. Using circular dichroism, we found that acidic pH did not induce significant conformational changes for HELP-4H.

Conclusions

Taken together, we were able to develop a new cationic histidine rich peptide able to efficiently deliver various nucleic acids into cells.