Dihexa

Dihexa

Dihexa (PNB-0408) — orally active angiotensin IV analogue; potentiates HGF/c-Met signaling to drive synaptogenesis 10⁷× more potently than BDNF in hippocampal models.

Description

Summary Abstract

Dihexa (PNB-0408; N-hexanoic-Tyr-Ile-(6) aminohexanoic amide; CAS 1401708-83-5; C27H44N4O5; MW 504.67 g/mol) is a synthetic oligopeptide engineered at Washington State University as a metabolically stabilized analogue of angiotensin IV (AngIV). Native AngIV is pharmacologically inert in practice because of a plasma half-life measured in seconds and negligible blood-brain barrier (BBB) permeability; Dihexa resolves both limitations through N-terminal hexanoylation and C-terminal aminohexanoic amide substitution, yielding a highly lipophilic, peptidase-resistant molecule with an IV half-life of approximately 12 days in rodents and confirmed tritium-labeled BBB penetration and brain accumulation. Dihexa binds hepatocyte growth factor (HGF) with a dissociation constant of 65 pM, potentiating HGF-induced dimerization and activation of its receptor c-Met (a receptor tyrosine kinase). Downstream PI3K/AKT and MEK/ERK signaling drives synaptogenesis seven orders of magnitude more potently than BDNF in hippocampal neuron cultures. Preclinical data demonstrate cognitive rescue in scopolamine-amnesia models, aged rats, APP/PS1 Alzheimer’s mice, and a 6-OHDA Parkinson’s model, alongside ototoxicity protection mediated by the same HGF/c-Met axis. A phosphate prodrug (Fosgonimeton/ATH-1017) entered Phase 2/3 trials (LIFT-AD); while primary clinical endpoints were not met, p-Tau217 biomarker reduction reached statistical significance (p < 0.01).

Clinical Indications

HGF/c-Met potentiation positions Dihexa across multiple neurological domains:

  • Alzheimer’s Disease and Neuroinflammation: Restores cognitive function in APP/PS1 models, reduces Iba-1-positive microglial activation, and decreases pro-inflammatory cytokines IL-1β and TNF-α while increasing protective IL-10.
  • Parkinson’s Disease: Preclinical evidence in 6-OHDA models suggests neuroprotection of dopaminergic neurons and potential neurogenesis from endogenous stem-cell pools.
  • Peripheral Nerve and Muscle Repair: Dihexa delivered via hydrogel to denervated muscles restores motor-unit size and attenuates post-transection atrophy in sciatic-nerve injury models.
  • Aminoglycoside-Induced Ototoxicity: HGF/c-Met-mediated protection of cochlear hair cells demonstrated in gentamicin-exposed zebrafish, suggesting a potential co-therapy application.
  • Mild Traumatic Brain Injury (mTBI): Rescue of working memory deficits and synaptic marker restoration following repeated mild concussive injury in rodent models.

Contraindications

  • Active Malignancy or High c-Met-Expressing Tumors: The HGF/c-Met axis is an established oncogenic pathway; potentiation carries a theoretical risk of promoting tumor growth in susceptible individuals.
  • Uncontrolled Hypertension / Prior Stroke: Angiotensin-system modulation warrants caution in subjects with unstable cardiovascular history.
  • Severe Psychiatric Disorders: Reports of overstimulation and anxiety correlate with rapid synaptic density increases; bipolar disorder, schizophrenia, and severe anxiety disorders may be exacerbated.
  • Pregnancy and Developmental Stages: HGF/c-Met is essential for embryonic morphogenesis; interference with this pathway carries unpredictable developmental risk.

Mechanism of Action (MOA)

Dihexa acts as a high-affinity positive allosteric modulator of the HGF/c-Met receptor tyrosine-kinase system, translating subthreshold growth-factor signals into full synaptogenic cascades:

HGF Dimerization Facilitation

Dihexa binds hepatocyte growth factor (HGF) with a Kd of 65 pM, facilitating HGF dimerization—a prerequisite for activation of the c-Met receptor tyrosine kinase. Even when endogenous HGF levels are insufficient to trigger a response, Dihexa enables c-Met phosphorylation, thereby amplifying the body’s endogenous regenerative signaling at physiologically relevant concentrations.

PI3K/AKT and MEK/ERK Downstream Activation

Activated c-Met initiates PI3K/AKT and MEK/ERK cascades central to neuronal survival, protein synthesis, and anti-inflammatory signaling. In hippocampal cultures, these pathways drive a nearly 3-fold increase in dendritic-spine density over five days, with newly formed spines confirmed functional via synaptophysin (SYP), VGLUT1, and PSD-95 expression. Effects are blocked by HGF antagonists and AKT/mTOR inhibitors, confirming pathway specificity.

Metabolic Stability via Structural Modification

N-terminal hexanoylation and C-terminal aminohexanoic amide substitution increase hydrophobicity and reduce hydrogen-bonding potential, enabling passive diffusion across BBB tight junctions. The modifications also provide steric protection against serum peptidases, extending plasma half-life to ~12 days (IV) and ~8.8 days (IP) in rodents — orders of magnitude beyond native AngIV’s seconds-scale stability.

Key Features & Specifications

Dihexa’s engineered pharmacokinetics address the key limitations of neuropeptide therapeutics:

Orally active, BBB-permeable peptide
10⁷× more potent than BDNF in synaptogenesis assays
IV half-life ~12 days (rodent)
HGF/c-Met selective — blocked by Hinge antagonist
Biomarker evidence: p-Tau217 reduction in Phase 2 trial
5 MG capsule format (SKU C-011)

Chemical Analysis

Property Specification Reference Data
IUPAC Name 6-[[2-[[1-(2-phenylacetyl)pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanamide (abbreviated; full name reflects hexanoyl–Tyr–Ile–aminohexanoic amide connectivity)
CAS Number 1401708-83-5
Molecular Formula C27H44N4O5
Molecular Weight 504.67 g/mol
PubChem CID 129010512
Synonyms PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, Dihexa
Form / Variation 5 MG Capsules (SKU C-011)

Storage, Safety, and Handling

Storage Protocol

Store capsules at 2–8 °C in a sealed container, protected from moisture and light. Lyophilized peptide retains structural integrity under these conditions; avoid freeze-thaw cycling of any reconstituted solutions. Capsule formulations should remain in original packaging until dispensed.

Handling & Compliance

Handle with standard laboratory PPE. The principal safety concern documented in the literature is the theoretical oncogenic risk arising from c-Met receptor potentiation; Dihexa’s allosteric mechanism limits activity to endogenous HGF availability, providing a partial ceiling, but the risk in subjects with undiagnosed malignancies cannot be fully excluded. No regulatory agency has approved Dihexa for clinical use; it is an investigational compound.