Cellular Translocation of a γ-AApeptide Mimetic of Tat Peptide

Cell-penetrating peptides including the trans-activating transcriptional activator (Tat) from HIV-1 have been used as carriers for intracellular delivery of a myriad of cargoes including drugs, molecular probes, DNAs and nanoparticles. Utilizing fluorescence flow cytometry and confocal fluorescence microscopy, we demonstrate that a gamma-AApeptide mimetic of Tat (48-57) can cross the cell membranes and enter the cytoplasm and nucleus of cells, with efficiency comparable to or better than that of Tat peptide (48-57). Deletion of the four side chains of the gamma-AApeptide attenuates translocation capability. We also establish that the gamma-AApeptide is even less toxic than the Tat peptide against mammalian cells. In addition to their low toxicity, gamma-AApeptides are resistant to protease degradation, which may prove to be advantageous over alpha-peptides for further development of molecular transporters for intracellular delivery.