Delivery of proteins and peptides into live cells by means of protein transduction domains: potential application to organ and cell transplantation.

Proteins are primary targets in drug discovery. However, with a few rare exceptions, they are unable to cross cell membranes, a limitation that prevents the full exploitation of their therapeutic potential. Major advances have been recently made through a novel approach of protein and peptide delivery into cells known as protein transduction or protein therapy. Proteins and peptides can be directly transferred to cells when covalently linked to protein transduction domains (PTD), small peptides that can freely cross cell membranes with low lytic activity (1–3). The mechanism of cellular translocation of PTD are currently poorly understood. Most of the PTD described in the literature have a high content of basic residues. It is believed that the interaction with the negative cell membrane environment has an important role in the translocation process, and the mechanism of cell internalization may differ for each of the PTD. Several PTD have been identified in naturally occurring proteins. The most commonly studied are homeodomain transcription factors such as antennapedia (4), the herpes simplex virus type 1 protein VP22 (5), and the human immunodeficiency virus (HIV) transactivator TAT protein (6–7). In addition, a new gamut of peptides with PTD capabilities have been recently identified. Some of these new peptides are derived from natural proteins, whereas others are synthetic peptides. The PTD included in these groups are described below, with emphasis on the TAT-PTD and its potential application in organ and cell transplantation.