Key Takeaways
- •Dihexa (PNB-0408) is a synthetic, metabolically stabilised analogue of angiotensin IV, molecular formula C₂₇H₄₄N₄O₅.
- •It is reported to bind hepatocyte growth factor (HGF) and potentiate HGF signalling at the c-Met receptor tyrosine kinase, rather than binding c-Met directly.
- •The 2014 paper central to that mechanistic model was retracted in 2025, so the mechanism is proposed rather than established.
- •A 2013 rodent study from the same research cluster carries a published notice of concern. It has not been retracted.
- •Almost the whole literature comes from one laboratory, and there are no published human clinical trials.
- •c-Met is a proto-oncogene receptor, and no published work characterises sustained potentiation of its signalling by this compound.
Summary
Dihexa is a synthetic analogue of angiotensin IV, built to be more lipophilic and more resistant to peptidases than the parent hexapeptide. It has been studied in cell culture and in rats, and it is approved nowhere, for anything.
The reason to read the rest of this carefully is that the ground under it moved. The 2014 paper that established the HGF/c-Met mechanism was retracted in 2025, and a 2013 rat study from the same group carries a published notice of concern. Neither has been replaced by independent work, because almost the whole literature comes from one laboratory.
So the mechanism should be described as proposed rather than established, and the open questions about sustained c-Met potentiation have not been addressed by anyone.
Evidence Quality Summary
| Evidence Area | Strength | Notes |
|---|---|---|
| Chemical identity | Strong | Defined synthetic structure, C₂₇H₄₄N₄O₅ |
| HGF/c-Met mechanism | Low | Key mechanistic paper retracted in 2025 |
| Rodent work | Low | Limited independent replication; notice of concern on a key study |
| Human data | None | No published human trials |
Quick Answers
| Question | Current Evidence |
|---|---|
| Human trials? | No published human clinical trials found |
| Main mechanism? | Proposed HGF binding and c-Met potentiation (partly contested) |
| Evidence type? | Cell culture and rodent models |
| Regulatory status? | Not approved anywhere, for any use |
What Is Dihexa?
Dihexa (also known as PNB-0408; formal name N-(1-oxohexyl)-L-tyrosyl-N-(6-amino-6-oxohexyl)-L-isoleucinamide; molecular formula C₂₇H₄₄N₄O₅) is a synthetic compound derived from angiotensin IV (Ang IV). Structurally it keeps the Tyr-Ile core of the Ang IV N-terminus, caps the N-terminus with a hexanoyl group and replaces the C-terminal residues with a 6-aminohexanoic amide. Those changes were made to raise lipophilicity and to remove the peptidase cleavage sites that make Ang IV short-lived.
Dihexa has been reported to bind hepatocyte growth factor (HGF) and potentiate HGF-dependent signalling at the c-Met receptor, although this mechanistic model rests partly on literature that has since been retracted (see below).
All published work on Dihexa is in vitro (cell culture) or in vivo (animal model). No human clinical trials have been published to date. Dihexa is a research compound and is not approved for human consumption.
Proposed Mechanism of Action
The proposed mechanism is the potentiation of HGF-dependent signalling at the c-Met receptor. Specifically, Dihexa has been reported to bind HGF and enhance its interaction with c-Met, rather than binding c-Met itself. That potentiation is reported to activate downstream PI3K/Akt and MAPK/ERK signalling in cultured cells.
Important caveat: the mechanistic model linking Dihexa to HGF/c-Met signalling rests substantially on a 2014 paper (Benoist et al., Journal of Pharmacology and Experimental Therapeutics) that was retracted in 2025. Because that paper was central to the proposed mechanism, claims about c-Met-dependent activity should be treated as provisional rather than established.
How the Literature Was Produced
The most widely cited rodent study is McCoy et al. (2013) in the Journal of Pharmacology and Experimental Therapeutics, which tested metabolically stabilised Ang IV analogues in aged rats. This article does not summarise its behavioural results, for two reasons that are about the evidence rather than the subject: that paper carries a published notice of concern, and its mechanistic interpretation leans on the paper that was later retracted.
The features that limit the literature as a whole:
- Single research group. Much of the published Dihexa literature originates from the laboratory of Dr. John W. Wright at Washington State University. Independent confirmation by other laboratories has not been widely reported in the peer-reviewed literature.
- Retracted literature. The 2014 Benoist et al. paper, which proposed that the effects of Ang IV-derived peptides depend on HGF/c-Met activation, was retracted in 2025.
- Notice of concern. The related 2013 McCoy et al. paper has a published notice of concern. It has not been retracted.
- Animal models only. No human pharmacokinetic or clinical data are available. As of a July 2026 search, no registered human clinical trial for Dihexa was identified on ClinicalTrials.gov.
- A small evidence base. The total number of published studies is small, and much of it is review rather than new experimental data. Wright and Harding (2015) is a review of the HGF/c-Met system in relation to Ang IV analogues and contains no new Dihexa experiments.
Open Safety Questions
Dihexa is a research chemical and is not approved for human consumption. No safety profile has been established.
- c-Met is a proto-oncogene. The HGF/c-Met pathway drives cell proliferation and is dysregulated in several tumour types. No published Dihexa work characterises sustained potentiation of that pathway.
- No toxicology programme. Metabolic pathways, half-life, organ-specific effects and interactions are uncharacterised.
- Design limits of the existing rodent work. The published studies were not designed to assess long-term toxicity, carcinogenicity or reproductive toxicity.
Current Research Status
Dihexa remains at an early preclinical stage. No clinical development programme has been publicly announced. Researchers working with Dihexa or related Ang IV analogues should monitor the publication and retraction status of cited literature and read every mechanistic claim in light of it. For context on evaluating research claims, see our Research Disclaimer.
Frequently Asked Questions
What is the proposed mechanism of Dihexa?
Dihexa has been reported to bind HGF and potentiate HGF-dependent signalling at the c-Met receptor. However, the key paper proposing this mechanism was retracted in 2025, so the mechanistic model should be considered provisional.
Has Dihexa been tested in humans?
No. All published research on Dihexa has been conducted in cell culture and rodent models. There are no human clinical trials, and no clinical development programme has been publicly announced.
What are the main limitations of the current evidence?
The evidence base is small, most studies originate from a single research group, independent replication is limited, a key mechanistic paper has been retracted, a key rodent study has a notice of concern, and there are no human data of any kind.
How does Dihexa differ structurally from angiotensin IV?
Angiotensin IV is the hexapeptide Val-Tyr-Ile-His-Pro-Phe. Dihexa keeps the Tyr-Ile core, replaces the N-terminal valine with a hexanoyl cap and replaces the C-terminal His-Pro-Phe with a 6-aminohexanoic amide, which removes the sites peptidases cleave and makes the molecule more lipophilic.
Is Dihexa approved for any medical use?
No. Dihexa is not approved by any regulatory agency for medical, therapeutic, or veterinary use. It is available only for laboratory research purposes. For related context, see our Peptide Glossary.
References
- McCoy, A. T., et al. (2013). Journal of Pharmacology and Experimental Therapeutics, 344(1), 141–154. DOI: 10.1124/jpet.112.199430 [Notice of Concern]
- Benoist, C. C., et al. (2014). Journal of Pharmacology and Experimental Therapeutics, 351(2), 390–402. [RETRACTED 2025]
- Wright, J. W., & Harding, J. W. (2015). Journal of Alzheimer's Disease, 45(4), 985–1000. A review of the brain HGF/c-Met system.
- Wright, J. W., & Harding, J. W. (2011). "Brain renin-angiotensin, a new look at an old system." Progress in Neurobiology, 95(1), 49–67.
Research-Only Disclaimer
Dihexa is sold for laboratory research purposes only, to qualified researchers and licensed laboratories. It is not approved for human consumption, medical use, or veterinary use. This article is for informational and educational purposes and does not constitute medical advice. Researchers must handle this compound in accordance with institutional biosafety guidelines and applicable regulations. For more information, please read our Research Disclaimer.
Reviewed by the Volta Peptides Research Team
