Adipotide (FTPP)

Adipotide, also called FTPP, is an experimental peptidomimetic made of two parts: a cyclic homing motif, CKGGRAKDC, that associates with prohibitin on blood vessels in white fat, and a proapoptotic sequence built from D-amino acids, (KLAKLAK)2. This listing is a 5 mg vial of freeze-dried powder. The published research on adipotide comes entirely from cell and animal studies, including one in obese monkeys.

How the molecule is built

The certificate writes adipotide as H-CKGGRAKDC-GG-klaklakklaklak-OH: 25 residues, with a disulfide between cysteine 1 and cysteine 9 that closes the first nine residues into a ring. Lower-case letters mark D-amino acids, so the fourteen-residue effector, two repeats of KLAKLAK, is made from the mirror-image forms of lysine, leucine and alanine. Two glycines link the halves, and both termini are free. The theoretical mass is 2555.2 Da, which makes 5 mg about 2.0 µmol before allowing for the water the certificate reports; the LC-MS identity result is the number to compare with it.

Each half has its own origin. CKGGRAKDC was found by in vivo phage display, a method that recovers peptides homing to particular vascular beds¹,². The KLAKLAK repeat matches de novo antimicrobial peptides designed to be perfectly amphipathic as helices³. Putting a homing domain and a proapoptotic domain into one short peptide follows the targeted proapoptotic peptides that Ellerby and colleagues described in 1999⁴.

What the research covers

Targeted proapoptotic peptides

Ellerby and colleagues introduced the approach in 1999 with short peptides built from two functional domains: a motif that homes to tumour blood vessels and a sequence that induces programmed cell death⁴. The proapoptotic domain was meant to be non-toxic outside cells and toxic once internalised, by disrupting mitochondrial membranes⁴. Their prototypes, of 21 and 26 residues, were selectively toxic to angiogenic endothelial cells and showed anti-cancer activity in mice⁴. The effector in adipotide matches a de novo antimicrobial design. Javadpour and colleagues made (KLAKLAK)n and related peptides as perfectly amphipathic helices and found that the 14-residue versions were bacteriostatic at micromolar concentrations, with much lower cytotoxicity toward mouse 3T3 fibroblasts and higher selectivity than the natural antimicrobial peptides magainin 2 and cecropin B; the 7-residue versions had neither activity nor secondary structure³.

An address in fat vasculature

Arap and colleagues developed in vivo phage display to find peptides that home to particular vascular beds, and in 2002 reported the first such screen in a patient, surveying 47,160 motifs and finding that circulating peptides distribute to organs non-randomly¹. With the same approach, Kolonin and colleagues isolated CKGGRAKDC as a motif homing to the vasculature of white fat, showed that it associates with prohibitin and proposed prohibitin as a vascular marker of adipose tissue². Aiming a proapoptotic peptide at prohibitin ablated white fat in their model, and they reported resorption of established fat and normalised metabolism without detectable adverse effects². Prohibitin was also found in blood vessels of human white fat².

The primate study

Barnhart and colleagues moved the work to primates, citing differences between rodents and primates as a major hurdle for translating anti-obesity strategies developed in rodents⁵. In obese Old World monkeys, adipotide induced targeted apoptosis in the blood vessels of white adipose tissue; the animals lost weight and their insulin resistance improved, and MRI and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue⁵. Monkeys of three species also showed predictable, reversible changes in renal proximal tubule function⁵. A 2011 review by Daquinag, Zhang and Kolonin set this work in a wider frame: white adipose tissue grows by adipocyte hypertrophy and hyperplasia that depend on angiogenesis, so its vasculature, or the stromal cells that support it, could be targeted⁶.

What is not established

All of the results above come from cell culture and animals, and none of the abstracts reports a human study of adipotide. The 2004 paper reported no detectable adverse effects, yet the monkey study found changes in kidney tubule function²,⁵. The prohibitin work traces largely to one group: Kolonin is an author on the phage display, fat ablation and review papers cited here¹,²,⁶. Adipotide is an experimental compound with no approved use, and none of these studies used SCALE Performance material.

Frequently asked questions

References

1. Arap W, Kolonin MG, Trepel M, et al. Steps toward mapping the human vasculature by phage display. Nat Med. 2002;8(2):121-7. DOI · PubMed
2. Kolonin MG, Saha PK, Chan L, et al. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10(6):625-32. DOI · PubMed
3. Javadpour MM, Juban MM, Lo WC, et al. De novo antimicrobial peptides with low mammalian cell toxicity. J Med Chem. 1996;39(16):3107-13. DOI · PubMed
4. Ellerby HM, Arap W, Ellerby LM, et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med. 1999;5(9):1032-8. DOI · PubMed
5. Barnhart KF, Christianson DR, Hanley PW, et al. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med. 2011;3(108):108ra112. DOI · PubMed
6. Daquinag AC, Zhang Y, Kolonin MG. Vascular targeting of adipose tissue as an anti-obesity approach. Trends Pharmacol Sci. 2011;32(5):300-7. DOI · PubMed