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AnimalTargeted fat-depot elimination via vascular apoptosis

FTPP Adipotide

Also indexed as Adipotide, CKGGRAKDC-GG-D(KLAKLAK)2, Prohibitin-targeting peptide

Adipotide is a pro-apoptotic peptidomimetic designed to selectively destroy the blood supply feeding white adipose tissue (WAT), causing fat cell death through targeted vascular disruption. It was developed at MD Anderson Cancer Center primarily as an anti-obesity compound and has shown dramatic fat loss in non-human primate studies. Human clinical data remains extremely limited, and it is considered a research compound only.

Overview

Following subcutaneous injection, the peptide enters systemic circulation with rapid distribution. The CKGGRAKDC moiety demonstrates ligand-receptor binding affinity for PHB at the luminal endothelial surface of WAT-feeding vessels. Following internalization via endocytosis, the D(KLAKLAK)2 domain inserts into and disrupts mitochondrial membranes, triggering intrinsic apoptosis. Vascular collapse leads to downstream ischemic adipocyte death. Renal filtration of peptide fragments and metabolic byproducts is believed to be responsible for the observed nephrotoxic effects, possibly via tubular accumulation.

Proposed mechanism

Adipotide consists of a targeting domain (CKGGRAKDC) that binds prohibitin, a protein selectively overexpressed on the luminal surface of blood vessels feeding white adipose tissue, fused via a GG linker to a pro-apoptotic domain (D(KLAKLAK)2) that disrupts mitochondrial membranes. Upon binding prohibitin on adipose vasculature endothelial cells, the apoptotic domain induces mitochondrial depolarization and cell death, collapsing the blood vessels that supply fat depots. The resulting ischemia causes programmed death of adipocytes and subsequent reduction in fat mass.

What the evidence supports

Most data comes from preclinical animal studies. Human clinical trial evidence is limited or absent.

Graded Animal

Evidence drawn from in vivo animal models or in vitro systems. Mechanistically informative; translation to humans is unproven.

Key citations

Representative primary sources, including results that did not favour the compound.

  1. [1]

    Reversal of obesity by targeted ablation of adipose tissue

    · Kolonin MG et al., Nature Medicine 10(6):625-632. doi:10.1038/nm1048 · 2004

  2. [2]

    Targeted apoptosis of adipose vasculature as an experimental therapy for obesity and metabolic disorders

    · Barnhart KF et al., Science Translational Medicine 3(108):108ra112. doi:10.1126/scitranslmed.3002155 · 2011

  3. [3]

    Prohibitin as a surface marker for targeting adipose vascular endothelium

    · Salameh A et al., related context from vascular biology literature · 2014

Citation records in this build are illustrative placeholders for the design.

Reference information for research purposes. Not medical advice, and not a recommendation to use any compound. Many entries describe substances that are not approved for human use.

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