Editorial [Hot Topic: Cell-Penetrating Peptides, Mechanisms and Applications (Executive Editor: Ulo Langel)]

This special issue of Current Pharmaceutical Design is dedicated to cell-penetrating peptides, CPPs, their mechanisms and applications. It is divided into seven chapters in which several aspects of cell-penetrating peptides are updated. This issue was compiled in November 2004 and reflects the concise summary of CPP research in recent 10 years since the first CPP, pAntennapedia (later named penetratin) was discovered by Alain Prochiantz' group in Paris in 1994 [1]. The precise definition of a CPP today remains controversial. CPPs are generally defined as short peptides translocating the plasma membrane in an endocytotic fashion as recently reported [2], as well as, in some cases, in a seemingly energy-independent manner[3], thus suggesting additional mechanisms of uptake. These mechanisms of CPP uptake find intensive attention in this special issue. However, alternative definitions and confusing naming of CPPs can be found in the literature, depending on the author and origin of the peptide. CPPs derived from proteins are often referred to as protein transduction domains, PTDs [4, 5]. Membrane-permeable sequences, MPS [6], and model amphipathic peptides, MAP [3], are additional examples of frequently used names for CPPs. In this issue, possible novel classes of CPPs, calcitonin-derived carrier peptides and vascular homing peptides with CPP properties, are described and summarized. Novel classes of CPPs are continually emerging and contribute strongly to the aims of CPP applications such as cell-targeted and in vivo delivery of drugs. An important CPP application is for the improvement of the uptake of genes and gene-silencing agents. Here, chapters addressing the improvement of oligonucleotide uptake by attachment to CPPs, or Bioplex entities, summarize recent achievements in the field. In summary, I hope that this special issue of the Journal will contribute strongly to our understanding and development of cell-penetrating peptides. References [1] Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 1994; 269: 10444-50. [2] Drin G, Cottin S, Blanc E, Rees AR, Temsamani J. Studies on the internalization mechanism of cationic cellpenetrating peptides. J Biol Chem 2003; 278: 31192-201. [3] Oehlke J, Scheller A, Wiesner B, Krause E, Beyermann M, Klauschenz E, Melzig M, Bienert M. Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta 1998; 1414: 127-39. [4] Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 1999; 285: 1569-72. [5] Mi Z, Mai J, Lu X, Robbins PD. Characterization of a class of cationic peptides able to facilitate efficient protein transduction in vitro and in vivo. Mol Ther 2000; 2: 339-47. [6] Chang M, Zhang L, Tam JP, Sanders-Bush E. Dissecting G protein-coupled receptor signalling pathways with membrane-permeable blocking peptides. J Biol Chem 2000; 275: 7021-9.