Adipotide (FTPP — Fat-Targeted Pro-apoptotic Peptide)

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What Is Adipotide / FTPP?

Adipotide (also called FTPP — “Fat-Targeted Pro-apoptotic Peptide”) is a synthetic 25-amino-acid chimeric peptidomimetic developed at the MD Anderson Cancer Center by Mikhail Kolonin, Wadih Arap, and Renata Pasqualini. The compound represents one of the cleanest examples of rational chimeric-peptide drug design in modern peptide pharmacology: a tissue-specific homing domain (identified by in-vivo phage display) is covalently fused to a generic killer domain (a pro-apoptotic mitochondrion-disrupting α-helical peptide), producing a chimera that delivers the killer activity selectively to the target tissue.

The two functional domains and the design logic:

1. CKGGRAKDC — the prohibitin-binding homing peptide. Kolonin et al. (2004) used in-vivo phage-display screening in obese mice to identify a 9-residue cyclic peptide (sequence Cys-Lys-Gly-Gly-Arg-Ala-Lys-Asp-Cys, with a Cys1-Cys9 disulfide bridge that constrains the geometry) that selectively binds the vasculature of white adipose tissue. The binding target was subsequently identified as prohibitin-1 (PHB1) — a normally mitochondrial-membrane-resident chaperone-like protein that, in white-adipose-tissue endothelium, is also expressed on the cell surface and accessible to circulating ligands. Annexin A2 has been identified as a secondary binding partner on the same vasculature. The CKGGRAKDC homing domain is the molecular zipcode that directs the chimera specifically to fat-tissue capillaries rather than to general systemic endothelium.

2. D(KLAKLAK)₂ — the pro-apoptotic α-helical killer peptide. The 14-residue D-amino-acid α-helical peptide D-Lys-D-Leu-D-Ala-D-Lys-D-Leu-D-Ala-D-Lys-D-Lys-D-Leu-D-Ala-D-Lys-D-Leu-D-Ala-D-Lys is a synthetic membrane-disrupting peptide (originally developed in cancer-targeting research by Ellerby et al. 1999). The amphipathic α-helical geometry causes the peptide to insert into membranes; the D-amino-acid stereochemistry confers protease-resistance in vivo. Crucially, the killer activity is niet selective for any particular cell type — the peptide will disrupt mitochondrial membranes in essentially any cell it gets inside — which is why pairing it with a homing domain is necessary for therapeutic utility.

3. GG linker. The two functional domains are joined by a simple di-glycine linker that provides flexible spacing and avoids steric interference between the homing and killer functions.

The combined chimera (CKGGRAKDC-GG-D(KLAKLAK)₂, ~2,611 Da) was characterised in obese rhesus monkeys in the landmark Barnhart et al. (2011) paper in Science Translational Medicine — animals lost approximately 11% body weight over 4 weeks of daily SC dosing, with concurrent improvements in insulin sensitivity. However, the same study and subsequent work documented dose-dependent nephrotoxicity: the kidney has high prohibitin expression and is densely vascularised, so off-target homing of the chimera to renal vasculature produces renal-cortex tubular damage. The MD Anderson group repositioned Adipotide for human oncology rather than obesity, and a Phase I clinical trial in patients with metastatic prostate cancer was conducted 2014–2016 with limited published outcomes. The compound remains a research tool today — extensively cited as a reference example of chimeric peptide drug design and the canonical pharmacological tool for studying targeted adipose-vascular apoptosis.

Mechanism of Action — Tissue-Targeted Apoptosis of Adipose Vasculature

Adipotide’s mechanism is one of the most-characterised in chimeric-peptide pharmacology:

• Vascular targeting via prohibitin-1 binding — The CKGGRAKDC homing domain binds prohibitin-1 expressed on the surface of capillary endothelial cells supplying white adipose tissue. Prohibitin-1 is normally a mitochondrial inner-membrane chaperone, but in WAT endothelium it is anomalously expressed on the plasma-membrane outer leaflet, making it accessible to circulating ligands. The CKGGRAKDC motif is highly selective for the WAT-endothelium prohibitin pool over other prohibitin expression contexts — published binding studies show ~10–100-fold enrichment of Adipotide in WAT vasculature over generic systemic vasculature.
• Annexin A2 as secondary binding partner — Subsequent published work has identified annexin A2 as an additional binding partner of the CKGGRAKDC homing domain on the same WAT endothelium. The dual prohibitin / annexin A2 recognition pattern may contribute to the selectivity profile of Adipotide.
• Internalisation and cytosolic delivery of the killer domain — After CKGGRAKDC binds the endothelial cell-surface receptors, the chimera is internalised by endocytosis. The amphipathic D(KLAKLAK)₂ domain is released into the cytosol via endosomal escape, and from there it accesses the mitochondrial outer membrane.
• Mitochondrial membrane disruption and apoptosis — The α-helical amphipathic geometry of D(KLAKLAK)₂ drives insertion into the mitochondrial outer membrane, with subsequent depolarisation, cytochrome c release, and activation of the intrinsic caspase apoptosis cascade. The D-amino-acid stereochemistry prevents proteolytic degradation of the killer peptide before it can reach its target.
• Vascular ablation → adipocyte starvation → fat-tissue mass loss — Apoptosis of the WAT-feeding endothelial cells starves adipocytes of blood supply. Over days to weeks, the adipocytes undergo their own secondary cell death by metabolic deprivation, and the adipose tissue shrinks. The macroscopic phenotype is dose-dependent body-weight reduction without the acute lipid-mobilisation seen with classical lipolytic agents like AOD-9604 or β3-adrenergic agonists.
• The nephrotoxicity problem — The kidney has very high vascular density and high prohibitin expression. Off-target homing of Adipotide to renal capillaries produces dose-dependent renal-cortex tubular damage in primate studies (Barnhart et al. 2011). This is the key translational limitation of the compound and the reason the obesity-pharmacology programme was discontinued in favour of cancer applications where a more aggressive risk-benefit balance is acceptable.

The combined mechanistic profile makes Adipotide uniquely useful for research on the vascular contribution to adipose-tissue biology — distinct from research on adipocyte-intrinsic lipolysis (the AOD-9604 / β3-AR axis) or GLP-1-mediated central appetite suppression (the semaglutide / GLP-1 family axis). Researchers studying angiogenesis-vs-anti-angiogenesis approaches to obesity, or testing other targeted-apoptosis peptide constructs, use Adipotide as the canonical positive-control compound.

Published Research Applications

Adipotide is used in laboratory research contexts that investigate:

• Chimeric peptide drug design — the canonical reference compound — by far the most-cited example of a tissue-targeted apoptotic chimera in published literature; standard reference compound for the broader “homing-peptide + killer-peptide” therapeutic-peptide design paradigm
• White adipose tissue vasculature research — Adipotide’s WAT-vasculature selectivity makes it the canonical tool for studying the role of vascular biology in adipose tissue mass regulation; used in research that explores whether obesity could be approached through anti-angiogenic / vascular-targeted strategies rather than appetite-suppressive or lipolytic strategies
• Prohibitin and annexin A2 biology — the homing-receptor identification work (Kolonin 2004 onward) established surface prohibitin as a vascular marker; Adipotide is the standard pharmacological tool for probing prohibitin-targeted approaches in primary endothelial culture and in-vivo work
• D-amino-acid pro-apoptotic peptide pharmacology — D(KLAKLAK)₂ is the most-cited pro-apoptotic D-peptide in the literature; Adipotide is the most-cited chimera incorporating it; widely used in research on protease-resistant peptide design
• Obesity-pharmacology comparative research — published head-to-head comparisons of Adipotide vs lipolytic peptides (AOD-9604), GLP-1 agonists (semaglutide, tirzepatide), and direct β3-AR agonists (mirabegron) characterise the different mechanism profiles for adipose-mass reduction
• Cancer / tumour-vasculature research — after the obesity programme was discontinued, Adipotide and related chimeras were repositioned for prostate-cancer research (Phase I trial 2014–2016); published research has explored the same homing-killer paradigm targeting tumour-specific endothelial markers (RGD-containing homing peptides + D(KLAKLAK)₂ for tumour-vasculature ablation)
• Targeted apoptosis pharmacology and drug-delivery research — Adipotide is the canonical positive-control compound for new tissue-targeted apoptosis peptide constructs (CPP-toxin chimeras, antibody-toxin conjugates with peptide warheads, etc.)
• Nephrotoxicity / vascular off-target research — the documented kidney toxicity is itself a research subject; published work has explored the basis of the renal off-target homing and tested second-generation Adipotide analogues with modified homing domains to reduce renal accumulation

For broader context on fat-loss and adipose-biology research peptides in this catalogue, see AOD-9604 (lipolytic-only hGH fragment — direct mechanism comparison; adipocyte-intrinsic vs vascular targeting), HGH Fragment 176-191 (the parent un-stabilised lipolytic fragment), Semaglutide (GLP-1 receptor agonist — central appetite suppression mechanism), Tirzepatide (dual GLP-1/GIP — broader metabolic effects), and MOTS-c (mitochondrial-derived metabolic peptide). Browse the full research peptides & compounds catalog, or see the curated fat-loss research peptides hub.

Beschikbare sterktes en concentraties

MedsBase stocks Adipotide / FTPP in three lyophilized vial sizes calibrated to typical in-vitro and in-vivo research protocols. Each strength is available in 10-vial or 20-vial pack formats:

All three strengths are the same chemical entity (lyophilized Adipotide / FTPP, ≥99% HPLC purity, MALDI-TOF mass-confirmed at ~2,611 Da, cyclic-disulfide-confirmed homing domain). The 10 mg vial provides the lowest per-mg cost for large in-vivo protocols. Researchers conducting any in-vivo work with Adipotide should plan comprehensive renal-function monitoring (BUN, creatinine, urinalysis, histology where appropriate) from the outset, given the well-documented nephrotoxicity profile in primate studies. Researchers should determine specific dose ranges from peer-reviewed literature appropriate to the protocol.

How It Compares — Adipotide vs AOD-9604

Adipotide and AOD-9604 are the two best-characterised fat-loss research peptides in this catalogue, and they target adipose-tissue biology through completely different mechanisms. Adipotide acts on the vasculature feeding adipose tissue — selectively ablating the WAT-endothelium via targeted apoptosis, starving adipocytes of blood supply. AOD-9604 acts on the adipocytes themselves — driving lipolysis and suppressing lipogenesis via a β3-AR-dependent mechanism (GHR-decoupled). The two compounds therefore probe completely different layers of adipose biology and are commonly used as positive controls in mechanism-of-action research.

For research focused on vascular contribution to adipose biology, chimeric peptide drug design, or targeted-apoptosis pharmacology, Adipotide is the canonical reference compound. For research focused on direct adipocyte lipolysis isolated from GH-axis signalling, AOD-9604 is the more targeted tool. The two compounds are mechanistically complementary and are commonly used as parallel positive controls in obesity-pharmacology mechanism research.

Opslag en Reconstituering

Voor reconstituering: store lyophilized vials refrigerated at 2–8 °C in original packaging for short-term working stock. For long-term storage, freeze unopened vials at −20 °C (stable ≥36 months at −20 °C; ≥18 months at 2–8 °C). The cyclic disulfide of the homing domain is stable in the lyophilized state. Protect from light.

Reconstitueringsprocedure: inject bacteriostatic water down the side wall of the vial (not directly onto the lyophilized cake). For a 2 mg vial, 1.0 mL of diluent yields a 2 mg/mL working stock. For a 5 mg vial, 1.0 mL yields 5 mg/mL; 2.5 mL yields 2 mg/mL. For a 10 mg vial, 1.0 mL yields 10 mg/mL (the practical solubility limit in aqueous buffer); 5.0 mL yields 2 mg/mL. Adipotide dissolves with gentle swirling at room temperature within 30–60 seconds; the amphipathic D(KLAKLAK)₂ domain may produce transient foaming on initial reconstitution — allow to settle before withdrawal. Do not vortex — high-shear mixing risks Cys1–Cys9 disulfide-bond disruption of the homing domain.

Once reconstituted, store the vial at 2–8 °C and use within 30 days. Protect from light. Avoid repeated freeze-thaw cycles of reconstituted material — cumulative cycles risk disulfide scrambling and loss of homing-domain target selectivity. Discard if cloudiness, particulates, or marked colour change appears.

Veelgestelde vragen

What is Adipotide and how is it different from other “fat-loss peptides”?

Adipotide (FTPP) is the canonical example of a vascular-targeted apoptosis approach to adipose-tissue reduction — completely mechanistically distinct from the lipolytic peptides (AOD-9604, β3-AR agonists), the central-appetite-suppression peptides (semaglutide, tirzepatide, the GLP-1 family), and the energy-balance peptides (MOTS-c). Where the lipolytic peptides activate adipocyte intrinsic lipid mobilisation, Adipotide ablates the blood supply to the adipocytes — a fundamentally different point of mechanistic intervention. It is the canonical research tool for studying the vascular contribution to adipose-tissue biology.

What is the documented nephrotoxicity, and what does it mean for research protocols?

Barnhart et al. (2011) and subsequent primate studies have documented dose-dependent renal-cortex tubular damage in Adipotide-treated rhesus monkeys. The mechanistic basis is straightforward: the kidney has very high vascular density and high prohibitin expression, so off-target homing of the chimera to renal capillaries produces the same vascular-apoptosis-then-starvation cascade as it produces in adipose tissue, but in a tissue where this is highly undesirable. This is the major translational limitation of the compound and is the reason the obesity-pharmacology programme was discontinued in favour of oncology repositioning (where a more aggressive risk-benefit balance is acceptable). Research protocols using Adipotide in vivo must include comprehensive renal-function monitoring — BUN, serum creatinine, urinalysis, and renal histology where appropriate.

What published dose ranges have been used in research?

The Kolonin et al. (2004) mouse work used 0.43 mg/kg/d SC for 4-week cycles. The Barnhart et al. (2011) rhesus-monkey work used the same 0.43 mg/kg/d SC for 4 weeks, with concurrent renal-function monitoring. The Phase I human prostate-cancer trial (2014–2016) used escalating SC doses on a weekly or twice-weekly schedule. In-vitro endothelial-cell apoptosis assays typically use micromolar concentrations. Researchers should consult primary literature (Kolonin et al. 2004, Nature Medicine; Barnhart et al. 2011, Science Translational Medicine) for species-, model-, and endpoint-specific dosing guidance.

What is the D-amino-acid stereochemistry of D(KLAKLAK)₂, and why does it matter?

The pro-apoptotic killer domain of Adipotide is synthesised exclusively in D-amino-acid stereochemistry — mirror-image versions of the natural L-amino acids. The reason is protease resistance: cellular and circulating proteases recognise and degrade peptides based on the natural L-amino-acid stereochemistry, so a D-amino-acid peptide is essentially invisible to host proteolysis. This protects the killer domain from premature degradation before it reaches its mitochondrial target. The homing domain (CKGGRAKDC) is in normal L-amino-acid stereochemistry because it must bind a host protein (prohibitin-1) in the canonical receptor-ligand geometry — D-stereochemistry would prevent binding entirely. This split-stereochemistry design (L-domain for binding + D-domain for protease-resistance) is a recurring motif in chimeric peptide drug design and is one of Adipotide’s most-cited features.

Why isn’t Adipotide FDA-approved?

Adipotide is a research compound that completed Phase I trials in human cancer patients (prostate cancer, 2014–2016) but has not progressed to large-scale Phase II/III trials. The reasons are a combination of the documented nephrotoxicity (which limits the dose window in any human-subject context), the modest published efficacy data in the limited clinical work to date, and the relatively narrow indication (vascular-targeted apoptosis is mechanism-appropriate for certain cancer settings but the broader development pathway is unclear). The compound remains a research tool today, widely used as the canonical chimeric peptide drug-design reference compound.

How is Adipotide different from AOD-9604?

Completely different mechanisms despite both being “fat-loss research peptides.” AOD-9604 is a 16-amino-acid hGH C-terminal fragment that activates lipolysis directly in adipocytes via the β3-adrenergic receptor (GHR-decoupled). Adipotide is a 25-amino-acid chimeric peptide that ablates the vascular blood supply to adipocytes via targeted endothelial apoptosis. AOD-9604 produces rapid acute lipolytic effects within hours; Adipotide produces slow tissue-mass reduction over days to weeks. AOD-9604 is generally well-tolerated; Adipotide has documented nephrotoxicity. Researchers studying obesity mechanisms often use both as parallel positive controls representing the two ends of the “adipocyte-intrinsic vs adipose-vascular” mechanistic spectrum.

Can Adipotide be combined with other fat-loss peptides in research protocols?

Yes — Adipotide is mechanistically orthogonal to lipolytic peptides (AOD-9604), GLP-1-axis peptides (semaglutide, tirzepatide), and metabolic peptides (MOTS-c), so combinations are mechanistically rational for research protocols that aim to dissect different layers of adipose biology. The most-published combinations in the limited literature are Adipotide + GLP-1 agonist (testing whether vascular ablation adds to appetite-suppression-driven weight loss). Reconstitute each separately and follow each compound’s specific storage rules. As always with Adipotide in vivo, comprehensive renal-function monitoring is required regardless of the co-administered compound.

What is the difference between Adipotide / FTPP and “prohibitin-targeting peptide-1” (PTP1)?

PTP1 is the homing-domain peptide alone — just the cyclic CKGGRAKDC sequence, without the pro-apoptotic D(KLAKLAK)₂ killer domain attached. PTP1 alone binds WAT-vasculature prohibitin-1 but does not trigger any apoptotic activity — it is just the molecular zipcode without the warhead. Adipotide / FTPP is the complete chimera (CKGGRAKDC + GG linker + D(KLAKLAK)₂) that combines the homing function with the killer function. Researchers studying the homing-domain biology in isolation use PTP1; researchers studying the integrated targeted-apoptosis effect use the full Adipotide chimera.

Other Research Peptides for Adipose Biology and Fat-Loss Research

• AOD-9604 — Lipolytic hGH C-terminal fragment — direct mechanism comparison; adipocyte-intrinsic vs vascular targeting
• HGH Fragment 176-191 — Un-stabilised lipolytic fragment — alternative adipocyte-direct lipolysis tool
• Semaglutide — GLP-1 receptor agonist — central appetite-suppression mechanism
• Tirzepatide — Dual GLP-1/GIP agonist — broader metabolic effects
• MOTS-c — Mitochondrial-derived metabolic peptide — alternative-mechanism fat-loss research
• BAC Water (Bacteriostatisch Water) — Required for reconstituting any lyophilized vial — sterile, 0.9% benzyl-alcohol-preserved diluent

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