Inhibtion of leukemia in vivo using a synthetic peptide.

Walensky et al. published a wonderful paper in Science (2004) 305: 1466-70 in which they develop a technqiue to enhance the alpha-helical folding of a peptide designed to stimualte apoptosis of leukemia cells. The peptide selected is the BH3 domain from the "BID" protein. I must admit I know nothing about these specific proteins or signaling pathways but the authors marshall an array of multidisciplinary studies that are dazzling and compelling to show that organic synthesis of a BH3 analog can produce a peptide with dramatically increased alpha-helical structure. They use CD spectroscopy to show that a hydrocarbon bridge of fixed length and conformation (8 carbons with a central cis double bond) between adjacent turns of the peptide alpha helix increases the alpha-helical content from 15 to 85%. This secondary structural motif is vital for the interaction with the down-stream targets, BAX and BAK (proteins that stimulate mitochodrial driven apoptosis). Not only does this enhancement increase the potency of the peptide, but it serves two other essential functions: (1) protects the peptide against degradation in vitro and in vivo; and (2) allows the peptide to penetrate the plasma membrane to the mitochodria. The authors use confocal microscopy, FACS analysis and multidimensional NMR to show how their "peptide stapling" technique works. The most striking results are saved till last. They find the mean survival of leukimic mice is increased from 5 to 11 days (total body luminescence is used to quantify tumor size). Thus, the study is a true multidisciplinary tour-de-force, encompassing many state of the arts technqiues, leading to a therapeutically important outcome.