Dihexa (N-Hexanoic-Tyr-Ile-(6) Aminohexanoic Amide)

Dihexa (PNB-0408) is a modified peptide derivative of angiotensin IV (Ang IV), developed at Washington State University by Dr. Joseph Harding's laboratory. Structurally it is N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide — Ang IV's bioactive core stabilized with hexanoic-acid modifications at both termini for protease resistance. Mechanistically, Dihexa binds hepatocyte growth factor (HGF) with picomolar affinity (Kd ≈ 65 pM) and potentiates HGF's activity at its receptor c-Met, driving downstream synaptogenesis, dendritic spine formation, and procognitive signaling. Critically, Dihexa demonstrates oral bioavailability and blood-brain barrier penetration in rodent models — properties that distinguish it from the vast majority of short peptides, which require parenteral administration to achieve meaningful CNS exposure.

Key Research Findings:

• In neurotrophic-activity assays, Dihexa was reported to be ~7 orders of magnitude (≈10-million-fold) more potent than BDNF at promoting new synapse formation in hippocampal cultures
• Binds HGF with high affinity (Kd ≈ 65 pM), positioning it as a positive allosteric potentiator of HGF/c-Met signaling rather than a direct c-Met agonist
• Aged-rat Morris water-maze studies showed significant restoration of spatial learning versus age-matched controls following oral administration
• Primary hippocampal neuron cultures exposed to Dihexa exhibited measurable increases in dendritic spine density within 24–48 hours of treatment
• Pharmacokinetic profiling in rats demonstrates oral bioavailability and measurable CNS exposure — uncommon for peptides of this size and a deliberate design goal of the hexanoic-acid terminal modifications

For laboratory and research use only.