Recent advances in protein transduction technology.

During the past 15 years, a variety of peptides, known as protein transduction domains (PTDs), or cell-penetrating peptides (CPPs), have been characterized for their ability to translocate into live cells. There are now numerous examples of biologically active full-length proteins and peptides that have been successfully delivered to cells and tissues, both in vitro and in vivo. One of the principal mechanisms of protein transduction is via electrostatic interactions with the plasma membrane, subsequent penetration into the cells by macropinocytosis, and release into the cytoplasm and nuclei by retrograde transport. Recent reports have also now shown that some of the limitations of protein transduction technology have been overcome. In particular, the use of ubiquitination-resistant proteins has been demonstrated to be a more effective strategy for transduction because the half-life of these molecules is significantly increased. Moreover, the use of the NH2-terminal domain of the influenza virus hemagglutinin-2 subunit (HA2) or photosensitive PTDs has been shown to specifically enhance macropinosome escape. Hence, these and other recent advances in protein transduction technologies have created a number of possibilities for the development of new peptide-based drugs.