Cell-penetrating peptides and their therapeutic applications

The process of introducing drugs into cells has always proved a major challenge for research scientists and for the pharmaceutical industry. The cell membrane is selectively permeable and supports no generic mechanism for their uptake. A drug must be either highly lipophilic or very small to stand a chance of cellular internalization. These restrictions mean that the repertoire of possible drug molecules is limited. Similarly, novel therapeutic approaches such as gene and protein therapy also have limited potential due to the cell-impermeable nature of peptides and oligonucleotides. The existing methods for delivery of macromolecules, such as viral vectors and membrane perturbation techniques, can result in high toxicity, immunogenicity and low delivery yield. However, in 1988 the remarkable ability of a peptide to traverse a cell’s plasma membrane independent of a membrane receptor was revealed. Known as Tat, the transcription activator of the human immunodeficiency virus type 1 (HIV-1) viral genome was shown to enter cells in a non-toxic and highly efficient manner. In light of such properties Tat became known as the first ‘cell-penetrating peptide’ (CPP). CPPs have demonstrated themselves to be capable of delivering biologically active cargo to the cell interior and the vehicular capabilities of CPPs have already been harnessed for use as laboratory tools. However, it is believed that their true potential lies within the field of therapeutics. Attached to a CPP, therapeutic cargo could be delivered to an intracellular target, thus overcoming the entry restrictions set by the plasma membrane. Since the discovery of Tat, the number of known peptides with cell-penetrating capabilities has grown and in 2003, the first CPP-based drug reached phase II clinical trials. This review discusses the controversial mechanism of entry employed by CPPs, their potential applications in vitro and in vivo, and the ways in which CPP properties have been optimized to maximize their potential as future therapeutics.