Adipotide

What Is Adipotide?

Adipotide (also called FTPP, Fat-Targeting Proapoptotic Peptide, or Prohibitin-Targeting Peptide 1) is a synthetic chimeric peptidomimetic with two domains joined together. The N-terminal CKGGRAKDC sequence is a vascular homing peptide that binds prohibitin-1 and annexin A2 on the endothelial cells lining the blood vessels that supply white adipose tissue. Once the peptide docks and is internalised, the C-terminal D(KLAKLAK)2 sequence, built from D-amino acids for protease resistance, inserts into the mitochondrial outer membrane of those endothelial cells, disrupts membrane integrity, releases cytochrome c, and triggers caspase-driven apoptosis.

The endothelial cells die, the capillary bed supplying that fat depot collapses, and the downstream adipocytes die from ischaemia. The mechanism is therefore targeted destruction of the vascular scaffolding fat depends on, not direct killing of fat cells. In the 2011 Science Translational Medicine primate study from the Arap and Pasqualini laboratory, obese rhesus monkeys lost about 11% of body weight over four weeks.

The critical limitation is that prohibitin is not exclusive to adipose vasculature. It is also expressed on the endothelium of renal vasculature, particularly the proximal tubule, so the same apoptotic mechanism damages renal capillaries and produces tubular toxicity, proteinuria, and rising creatinine. The therapeutic window between adipose-vessel ablation and renal injury proved narrow in primates, and the Phase 1 human trial at MD Anderson was terminated for renal toxicity.