Dihexa

A metabolically stabilised angiotensin IV analogue (developmental code PNB-0408) that potentiates hepatocyte growth factor signalling at the c-Met receptor and drives dendritic spine formation at picomolar concentrations in preclinical models.

What it is

Dihexa is a small, N- and C-terminal modified oligopeptide derived from angiotensin IV, with the chemical name N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide. It was developed by Joseph Harding, John Wright and colleagues at Washington State University as part of a program to convert the procognitive angiotensin IV analogue Nle(1)-AngIV into an orally active, blood-brain-barrier-penetrant drug candidate. Structurally it caps a tyrosine-isoleucine core with a hexanoic acid group at the N-terminus and a 6-aminohexanoic amide at the C-terminus, changes that make the molecule hydrophobic, metabolically stable and small enough to cross into the brain.

Dihexa is classed as a hepatocyte growth factor (HGF) mimetic or c-Met potentiator. Its phosphate pro-drug, fosgonimeton (ATH-1017), was carried into human clinical trials for Alzheimer\'s disease by Athira Pharma, giving dihexa itself an unusually well characterised preclinical record for a research peptide. Supplied strictly for laboratory research use only, not for human or veterinary use.

How it works

Dihexa binds hepatocyte growth factor with high affinity, a reported dissociation constant of around 6.5 x 10^-11 M, and acts as a positive modulator of the HGF / c-Met receptor tyrosine kinase system rather than a direct receptor agonist. In cell assays dihexa alone produces little c-Met phosphorylation, but in the presence of sub-threshold amounts of HGF it augments c-Met activation and downstream signalling, effectively lowering the concentration of HGF needed to trigger a biological response. This mirrors the behaviour of its parent compound Nle(1)-AngIV.

Downstream, the potentiated HGF/c-Met signal feeds into pathways associated with neuronal growth and plasticity, including the PI3K/AKT cascade, and translates into new dendritic spines and functional synapses in hippocampal neurons. Because the effect works through an endogenous growth-factor system that is active at very low ligand concentrations, dihexa is reported to be effective at picomolar levels, and secondary sources describe it as roughly seven orders of magnitude more potent than brain-derived neurotrophic factor in neurotrophic assays.

What the research shows

The core preclinical evidence comes from McCoy and colleagues (2013, Journal of Pharmacology and Experimental Therapeutics), who characterised dihexa as a metabolically stabilised, orally active Nle(1)-AngIV derivative. In cultured hippocampal neurons picomolar dihexa produced a near three-fold increase in dendritic spine number, and orally dosed dihexa reversed a scopolamine-induced learning deficit in the Morris water maze and improved performance in aged rats. A later study in the APP/PS1 Alzheimer\'s mouse model reported rescue of cognitive impairment linked to PI3K/AKT signalling. All figures below are from animal or cell studies; there is no established human efficacy.

Clinical translation

Dihexa\'s phosphate pro-drug fosgonimeton (ATH-1017) was advanced by Athira Pharma into controlled human trials for Alzheimer\'s disease. In the Phase 2/3 LIFT-AD study of 315 participants, once-daily subcutaneous fosgonimeton 40 mg was generally well tolerated but did not meet its primary or key secondary endpoints at 26 weeks: the change in ADAS-Cog11 was -1.09 for fosgonimeton versus -0.39 for placebo, a difference of -0.70 that was not statistically significant (P = 0.35). These human data apply to the pro-drug, not to dihexa as sold for research, and underline that the compelling rodent findings have not translated into demonstrated clinical benefit.

At a glance

Preparing it

Dihexa is typically supplied as a lyophilised powder for reconstitution in the laboratory. It is markedly hydrophobic, so handlers commonly note that plain bacteriostatic water alone dissolves it poorly and a small co-solvent step may be required before dilution. For the general method and for working out target concentrations, see the reconstitution guide and the concentration guide. Store the sealed vial cold, generally 2-8 C, and protect from light.

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