Cell Penetrating Peptides

Cell penetrating peptides, CPPs, are frequently used to deliver peptide cargo into cells where they can exert their biological activity. Their success, however, can be dependent on the cargo, the cell type, and other variables of peptide application. Published in Peptide Science, researchers in the Wilce Group, describe the preparation of a bicyclic peptide inhibitor of the Grb7 cancer target and its conjugation via click chemistry to FITC‐labeled derivatives of the classic CPP Penetratin, as well as the equivalent with an additional nuclear localization signal, NLS. The group members discovered that uptake of the cargo‐Penetratin into the breast cancer cell line MDA‐MB‐231 was slow and led to limited cytosolic distribution. However, the addition of the NLS greatly enhanced the delivery leading to both cytosolic and nuclear distribution.

Overall, the group members have shown that click chemistry can be utilized for the cellular delivery of a bicyclic intracellular targeted peptide. They also have shown that the inclusion of an NLS sequence can act to enhance cellular delivery. Whether the inclusion of an NLS represents a universal solution to the problem of cell delivery is yet to be determined. In many cases nuclear delivery would not be the desired destination for the cargo. 

It is also yet to be ascertained whether such constructs show cellular toxicity. It has been shown that while the Penetratin CPP is relatively non‐toxic to cells, CPPs of different composition have displayed increasing degrees of toxicity.42 However, if Penetratin‐NLS is established as nontoxic to the target cell, it may well prove to be a superior delivery agent compared to Penetratin for some cell types or under particular circumstances.


Preparation and Cellular Uptake of Bicyclic‐Peptide Cargo Clicked to Cell Penetrating Peptides
Ketav Kulkarni, Gabrielle M. Watson, Jianrong Sang, Jacqueline A. Wilce
PEPTIDE SCIENCE, Volume 110, Issue 3