Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.
This article explains what dihexa is chemically and why it is not a peptide in the sense the rest of this catalog uses the word, where it came from, what the hepatocyte growth factor (HGF)/c-Met hypothesis claims, how thin and how troubled the supporting literature is, including three retractions in 2025, and what that means for a laboratory deciding whether to buy it.
What dihexa is chemically
Dihexa is the common name for N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, also coded PNB-0408. It is a small molecule of 504.7 Da with the formula C27H44N4O5, indexed as PubChem CID 129010512 and CAS 1401708-83-5. Reading the name from left to right: a hexanoyl (six-carbon fatty acyl) cap on the N-terminus, a tyrosine, an isoleucine, and then a 6-aminohexanoic acid spacer ending in a primary amide. Only one bond in the molecule, Tyr-Ile, is a peptide bond between two proteinogenic amino acids. The rest is a fatty-acid amide at one end and a non-natural ω-amino acid at the other. That is why we class it with small molecules rather than peptides: it is not made by standard solid-phase peptide synthesis from a sequence, it does not have a sequence in the usual sense, and its analytics are those of a 500 Da organic compound rather than a 2 to 5 kDa polypeptide. Our peptide primer explains where the boundary sits.
| Compound | Structure | Mass (Da) | Class |
|---|---|---|---|
| Angiotensin IV | Val-Tyr-Ile-His-Pro-Phe | 775 | Native hexapeptide (fragment of angiotensin II) |
| Nle1-angiotensin IV | Nle-Tyr-Ile-His-Pro-Phe | ~789 | Stabilized hexapeptide analog |
| Dihexa (PNB-0408) | Hexanoyl-Tyr-Ile-NH-(CH2)5-CONH2 | 504.7 | Capped dipeptide mimic; small molecule |
| Typical research peptide (e.g. BPC-157) | 15 to 40 proteinogenic residues | 1,400 to 5,000 | Polypeptide made by solid-phase synthesis |
Where it came from: angiotensin IV and the AT4 site
Dihexa descends from angiotensin IV, the hexapeptide Val-Tyr-Ile-His-Pro-Phe produced when aminopeptidases trim angiotensin II. Angiotensin IV binds a high-affinity site in brain tissue that was named the AT4 receptor before its identity was known. A 2001 Journal of Biological Chemistry paper by Albiston and colleagues purified that binding site and identified it as insulin-regulated aminopeptidase (IRAP), a membrane enzyme; angiotensin IV and the related ligand LVV-hemorphin-7 competed for binding in transfected HEK 293T cells and inhibited the enzyme's catalytic activity. That is the mainstream identity of the AT4 site and it is still the position of most of the field.
A separate line of work in the laboratory of Joseph Harding and John Wright at Washington State University pursued stabilized angiotensin IV analogs. The core claim, stated in the 2013 JPET paper by McCoy and colleagues, was that the activity of Nle1-angiotensin IV resides in its three N-terminal residues, Nle-Tyr-Ile, and that capping and modifying that fragment could produce a molecule with far better stability and barrier permeability. Dihexa was the product of that series: the paper reports the N- and C-terminal modifications, the stability gains, behavior in rat Morris water maze tasks after scopolamine and in aged rats, and spine and synapse counts in cultured hippocampal neurons. Everything in that description is rodent or cell culture; there has never been a human study of dihexa.
The HGF/c-Met hypothesis
The Harding/Wright group proposed that angiotensin IV analogs act not through IRAP but by modulating hepatocyte growth factor and its receptor c-Met. The sequence of papers was: a 2010 JPET study (Yamamoto and colleagues) reporting that the analog norleual competed with HGF for binding in mouse liver membranes and blocked HGF-dependent signaling, and that it produced responses in HEK cells lacking IRAP; a 2011 JPET paper (Kawas and colleagues) proposing norleual mimics the HGF dimerization "hinge" region; a 2012 JPET paper describing the 6-aminohexanoic amide family as HGF-binding "Met modifiers"; and the 2014 JPET paper by Benoist and colleagues reporting that dihexa bound HGF with high affinity, raised c-Met phosphorylation in the presence of sub-threshold HGF, drove spinogenesis in hippocampal cultures, and that these effects were blocked by an HGF antagonist and by short-hairpin RNA against c-Met. Two 2015 reviews by Wright and Harding, in the Journal of Alzheimer's Disease and Progress in Neurobiology, assembled this into the claim that dihexa is an allosteric HGF mimetic. The Progress in Neurobiology review itself acknowledges that the identity of the AT4 site is contested and that Albiston's IRAP evidence is convincing.
What a reader should notice is that every primary paper supporting the HGF/c-Met mechanism came from a single laboratory group, that the mechanism was inferred from binding and signaling assays with recombinant HGF plus pharmacological blockers, and that no independent group has reproduced the direct dihexa-HGF binding result.
Notices of concern and retractions
In 2021 JPET published Notices of Concern on four papers from the group: Kawas 2011, Kawas 2012, McCoy 2013 and Benoist 2014. In 2025 the journal retracted three of them, Kawas 2011, Kawas 2012 and Benoist 2014. The 2013 McCoy paper that first described dihexa remains published under a Notice of Concern. The notices should be read directly; this article does not characterize the reasons beyond what the journal has published. The consequence for anyone reading the literature is plain: the paper that reported dihexa binding HGF and the two papers that established the hinge-mimic idea for this chemical family are no longer part of the valid record, and the first synthesis paper carries an unresolved flag.
| Paper | Role in the dihexa story | Status |
|---|---|---|
| Yamamoto et al., JPET 2010 | Norleual as HGF/c-Met inhibitor; doubt cast on IRAP | Published |
| Kawas et al., JPET 2011 | HGF hinge-region mimic concept | Notice of Concern 2021; retracted 2025 |
| Kawas et al., JPET 2012 | 6-aminohexanoic amide family as Met modifiers | Notice of Concern 2021; retracted 2025 |
| McCoy et al., JPET 2013 | First description of dihexa; rat and culture models | Notice of Concern 2021; still published |
| Benoist et al., JPET 2014 | Dihexa binds HGF; c-Met dependence | Notice of Concern 2021; retracted 2025 |
Work from other groups
A handful of later papers used dihexa outside the originating laboratory, and together they do not add up to a validated mechanism. A 2015 Frontiers in Cellular Neuroscience study (Uribe and colleagues, with Harding as a co-author) exposed zebrafish lateral-line hair cells to aminoglycosides with and without dihexa and reported that protection was reduced by an HGF antagonist and by inhibitors of Akt, TOR and MEK. A 2021 Brain Sciences paper from a Chinese group (Sun and colleagues) studied dihexa in APP/PS1 transgenic mice and attributed its effects to the PI3K/AKT pathway rather than to HGF/c-Met. A 2021 rat sciatic-nerve transection study (Weiss and colleagues, Annals of Medicine and Surgery) tested dihexa alongside mesenchymal stem cells and G-CSF. A 2024 Journal of Huntington's Disease study (Wells and colleagues) gave dihexa (as PNB-0408) to rats in the 3-nitropropionic acid model and reported that it did not attenuate the induced deficits, a null result. A 2018 systematic review of angiotensin IV and angiotensin-(1-7) experimental studies by Ho and Nation in Neuroscience and Biobehavioral Reviews placed the whole angiotensin IV analog field in the rodent-only category. PubMed returns fewer than twenty records for "dihexa", none of them human.
Why many vendors do not carry it, and what a certificate should show
Dihexa sits outside what most research-peptide suppliers are set up to source, test and defend. It is made by solution-phase organic synthesis, not solid-phase peptide synthesis, so a peptide manufacturer's standard identity and purity workflow does not fit it; identity is a single-charge LC-MS peak at m/z 505.3 for [M+H]+ rather than a multiply charged envelope, and purity is an HPLC-UV area-percent on a hydrophobic small molecule. The hexanoyl cap makes it poorly soluble in water, so stock solutions are typically prepared in DMSO, which is a different handling regime from a lyophilized peptide. The literature is one-lab, rodent-only, and partially retracted, so there is little a supplier can honestly point to. And the compound has no development history: no sponsor, no investigational application, no regulatory filing and no approved product anywhere. For most vendors the combination of low demand, unusual analytics and reputational risk is enough to leave it off the list.
US Prime Peptides carries Dihexa 5 mg for laboratories that have a defined in vitro question, with a lot-matched certificate that reports identity by mass spectrometry against the 504.7 Da expected mass, purity by HPLC, content, endotoxin, sterility and heavy metals, issued by an independent US laboratory and posted before purchase. Our LC-MS article explains why a small molecule's spectrum looks different from a peptide's, and our vendor checklist covers how to weigh a thin literature when deciding what to buy.
Frequently Asked Questions
Is dihexa a peptide?
Not in the catalog sense. Dihexa is a 504.7 Da small molecule with one true peptide bond (Tyr-Ile), a hexanoyl cap at one end and a 6-aminohexanoic amide at the other. It is made by solution-phase organic synthesis and analyzed like a small molecule, not like a 2 to 5 kDa polypeptide.
What is the HGF/c-Met hypothesis for dihexa?
The Harding/Wright laboratory proposed that dihexa binds hepatocyte growth factor and enhances activation of its receptor c-Met, based on binding, phosphorylation and cell-culture experiments reported in JPET in 2014. That paper, and the two 2011 and 2012 papers that set up the idea, were retracted by the journal in 2025.
Has dihexa been studied in humans?
No. Every published dihexa study is in rodents, zebrafish larvae or cell culture. There is no sponsor, no investigational application and no regulatory filing for the compound in any country, and it is not an approved drug.
Why was the dihexa research retracted?
The journal JPET issued Notices of Concern on four papers from the originating group in 2021 and retracted three of them in 2025 (Kawas 2011, Kawas 2012, Benoist 2014). The journal's notices are the authoritative statement of the reasons; the 2013 McCoy paper that first described dihexa remains published under its notice.
Citations
- McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141-154. Notice of Concern issued 2021. PMID 23055539
- Albiston AL, McDowall SG, Matsacos D, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001;276(52):48623-48626. PMID 11707427
- Yamamoto BJ, Elias PD, Masino JA, et al. The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor. J Pharmacol Exp Ther. 2010;333(1):161-173. PMID 20086056
- Benoist CC, Kawas LH, Zhu M, et al. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014;351(2):390-402. RETRACTED 2025. PMID 25187433
- Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" [J Pharmacol Exp Ther 351 (2014) 390-402]. J Pharmacol Exp Ther. 2025;392(5):103567. PMID 40312093
- Notice of Concern: McCoy AT, Benoist CC, Wright JW, et al. (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents. J Pharmacol Exp Ther. 2021;378(3):313. PMID 34551989
- Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. PMID 25649658
- Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol. 2015;125:26-46. PMID 25455861
- Sun X, Deng Y, Fu X, et al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021;11(11):1487. PMID 34827486
- Wells RG, Azzam AF, Hiller AL, et al. Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats. J Huntingtons Dis. 2024;13(1):55-66. PMID 38489193
- Uribe PM, Kawas LH, Harding JW, Coffin AB. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015;9:3. PMID 25674052
- Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neurosci Biobehav Rev. 2018;92:209-225. PMID 29733881
This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.
Related research
Compliance Notice: US Prime Peptides products are supplied strictly for laboratory and academic research purposes only. They are not intended for human or veterinary consumption, diagnosis, treatment, or prevention of any disease. All content on this page is educational in nature and does not constitute medical advice or product claims. Researchers are responsible for handling these compounds in accordance with their institution’s safety protocols and applicable laws.
