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Synthetic Protein Transduction Domains: Enhanced Transduction Potential in Vitro and in Vivo¹

Howard Hughes Medical Institute and Departments of Pathology and Medicine [A. H., S. R. S., S. J. M., S. F. D.], and Department of Biochemistry and Molecular Biophysics [G. W.], Washington University School of Medicine, St. Louis, Missouri 63110

The protein transduction domain (PTD) embedded in the HIV TAT protein (amino acids 47–57) has been shown to successfully mediate the introduction of heterologous peptides and proteins in excess of M_r 100,000 into mammalian cells in vitro and in vivo. We report here that the modeled structure of the TAT PTD is a strong amphipathic helix. On the basis of this information, we synthesized a series of synthetic PTDs that strengthen the -helical content and optimize the placement of arginine residues. Several PTD peptides possessed significantly enhanced protein transduction potential compared with TAT in vitro and in vivo. These optimized PTDs have the potential to deliver both existing and novel anticancer therapeutics.

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