Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo.
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 Mr 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 alpha-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.
Ho
A
A
Howard Hughes Medical Institute and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Schwarze
S R
SR
Mermelstein
S J
SJ
Waksman
G
G
Dowdy
S F
SF
D000595:Amino Acid Sequence; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*
D015696:Gene Products, tat; D009842:Oligopeptides; D016650:Fluorescein-5-isothiocyanate