Davunetide: brain-protecting peptide (NAPVSIPQ)
A tiny peptide snipped from a critical brain protein that shields neurons from damage; studied in clinical trials for neurodegenerative and cognitive conditions, but not yet an approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
Named peptide fragment — synthesized for research; ClinicalTrials.gov trials registered for parent compound or class
Fork this card to add platform evidence →
Endogenous peptide fragment — receptor binding/activity established in published literature; CT.gov evidence
Fork this card to add platform evidence →
What this is
NAP (also called davunetide or CP201) is a tiny 8-amino-acid peptide — the sequence NAPVSIPQ — snipped out of a much larger brain protein called ADNP (Activity-Dependent Neuroprotective Protein). Despite its small size, it protects neurons at extraordinarily low concentrations, active in the femtomolar range (10⁻¹⁵ M) that are far below most drugs. The ADNP gene is essential for mammalian brain formation: complete loss of ADNP in mice is embryonic-lethal, while partial loss causes cognitive deficits. NAP carries the key neuroprotective activity of the parent protein and has been studied in human clinical trials for several neurodegenerative and cognitive conditions.
History
ADNP was discovered in the Gozes laboratory at Tel Aviv University around 1999. The initial line of inquiry began with vasoactive intestinal peptide (VIP), a neuropeptide that had long been known to protect neurons and promote synapse formation through glial activation. Searching for proteins regulated by VIP in cerebral cortical astrocytes, Gozes and colleagues identified a novel 828-amino-acid protein they named Activity-Dependent Neuroprotective Protein — ADNP. Peptide activity scanning of the ADNP sequence located a short 8-residue motif, NAPVSIPQ, that retained the parent protein's neuroprotective activity at femtomolar concentrations. This fragment was named NAP after the first three residues of its sequence (Gozes and colleagues, Annals of the New York Academy of Sciences, 1999).
Development of NAP as a drug candidate was taken up by Allon Therapeutics (Vancouver, Canada), which developed an intranasal formulation known as AL-108, and later advanced the compound under the name davunetide into Phase 1, Phase 2, and Phase 2/3 trials. After Allon Therapeutics became insolvent and was acquired by Paladin Labs in 2013, clinical development stalled. Interest was revived when ADNP mutations were identified in 2012–2014 as a cause of a rare neurodevelopmental disorder now called ADNP syndrome (Helsmoortel-Van der Aa syndrome). Exonavis Therapeutics licensed davunetide from Tel Aviv University in 2021 and has been pursuing it as a treatment for children with ADNP syndrome, with a Phase 3 trial begun in October 2024.
What it does
In cell culture and animal models, NAP protects neurons against a broad range of insults — beta-amyloid peptide toxicity, oxidative stress, stroke, closed head injury, glucose deprivation, HIV envelope protein toxicity, and zinc overload, among others. In mouse models of Alzheimer's disease, treatment reduced accumulation of hyperphosphorylated tau and improved cognitive performance (Matsuoka and colleagues, 2008). In a mouse model of alpha-synuclein overexpression relevant to Parkinson's disease, short-term NAP treatment improved motor function and reduced alpha-synuclein inclusions. NAP has also shown protection against ethanol-induced fetal developmental toxicity in mouse embryo models, with half-maximal effects at 36 fM, traced to antagonism of ethanol's disruption of L1-mediated cell adhesion (Wilkemeyer and colleagues, 2003).
The compound crosses the blood-brain barrier after both intranasal and intravenous administration, reaching the cerebrospinal fluid.
Mechanism
NAP contains an SxIP motif (the Ser-Ile-Pro region that is essential for its activity) that directly engages EB1 and EB3 — end-binding proteins that sit at the growing tips of microtubules and serve as master regulators of the microtubule cytoskeleton. By binding to EB1 and EB3, NAP promotes microtubule assembly and stabilizes the cytoskeletal network inside neurons. Silencing EB1 and EB3 (but not EB2) abolishes NAP's neuroprotective activity, confirming these proteins as the critical mediators.
The downstream consequence of this microtubule stabilization is protection against tau pathology. NAP inhibits tau hyperphosphorylation at serine 262 — a site whose phosphorylation impairs tau's ability to bind EB proteins — and produces striking increases (described as approximately 20-fold) in EB1/EB3–tau interactions, recruiting tau back to microtubules under stress conditions (Gozes group, Molecular Psychiatry, 2016). This mechanism distinguishes NAP from conventional tubulin-targeting cytotoxic drugs: it acts selectively on brain-derived tubulin without affecting proliferating cells, and no adverse effects were observed after six months of exposure in animal models.
ADNP itself functions as a chromatin remodeler and transcription factor, interacting with the SWI/SNF chromatin remodeling complex. The NAP fragment captures the microtubule-interacting dimension of ADNP biology.
Evidence
- Human: Phase 2 trial in amnestic mild cognitive impairment (144 subjects, placebo-controlled, intranasal NAP) showed statistically significant improvement in memory performance versus placebo at 8 and 16 weeks (Gozes and colleagues, 2009). Phase 2 trial in schizophrenia (63 patients) missed the primary composite cognitive battery endpoint but showed significant improvement on a functional capacity measure (UPSA scale); MRS substudy in DLPFC found modest increases in N-acetylaspartate and choline ratios consistent with a neuroprotective signal (Neuropsychopharmacology, 2013). Phase 2/3 trial in progressive supranuclear palsy (Boxer and colleagues, Lancet Neurology, 2014): 313 participants randomized 1:1 to davunetide 30 mg intranasal twice daily or placebo for 52 weeks across 47 sites; the trial found no difference on either primary endpoint (PSP Rating Scale or Schwab–England Activities of Daily Living), establishing that davunetide is not effective for PSP. A Phase 3 trial in children with ADNP syndrome (97 participants, ExoNavis) began October 2024; results are pending.
- Animal: Reduced tau hyperphosphorylation and improved cognition in transgenic Alzheimer's mouse models; improved motor function and reduced alpha-synuclein inclusions in synucleinopathy mouse models; neuroprotection across stroke, head injury, apolipoprotein E-deficiency, and cholinergic toxicity models.
- In vitro: Protection at femtomolar concentrations against beta-amyloid, NMDA, oxidative stress, HIV gp120, and zinc toxicity in neuronal cultures; promotion of microtubule assembly and neurite outgrowth in cellular models (Gozes and Divinski, Current Alzheimer's Research, 2007).
Known effects
- Neuroprotection (broad-spectrum) — Preclinical; demonstrated against multiple distinct neurotoxic insults in vitro and in vivo
- Tau pathology reduction — Preclinical (AD mouse models); reduced hyperphosphorylated tau and cognitive improvement
- Microtubule stabilization — Mechanistic; well-characterized via EB1/EB3 interaction and direct tubulin binding
- Memory improvement (MCI) — Phase 2 human signal (short-term, 8–16 weeks); not replicated in larger trials
- Functional capacity in schizophrenia — Phase 2 human signal (UPSA endpoint); composite cognition endpoint not met
- PSP treatment — Phase 2/3 negative; not effective for progressive supranuclear palsy
- Alpha-synuclein pathology reduction — Preclinical only (mouse model)
Safety signals
Across Phase 1 and Phase 2 human trials in adults, NAP/davunetide was generally reported as safe and well tolerated. Non-clinical toxicology studies at doses up to 300 mg/kg/day in rats, dogs, and mice showed no significant adverse events, providing the safety basis for clinical entry. In the Phase 2/3 PSP trial (Boxer and colleagues, Lancet Neurology, 2014), nasal adverse events were more frequent in the davunetide group than placebo: epistaxis (12% vs. 8%), rhinorrhoea (10% vs. 5%), and nasal discomfort (10% vs. less than 1%). Serious adverse event rates were similar between groups (54 per arm), including 11 deaths in the davunetide arm and 10 in the placebo arm, with no drug-attributed mortality signal identified. No adverse proliferative or cytotoxic effects on non-neuronal tissues have been reported in preclinical studies, consistent with the compound's selectivity for brain-derived tubulin.
Regulatory status
- US: Investigational. No FDA approval. FDA Orphan Drug Designation and Rare Pediatric Disease Designation granted for ADNP syndrome treatment.
- EU: EMA Orphan Drug Designation for ADNP syndrome.
- WADA: Not listed on the WADA Prohibited List (not a performance-relevant compound).
Related peptides
NAP (NAPVSIPQ) belongs to the family of ADNP-derived neuropeptides. A companion peptide SAL (SALLRSIPA), also derived from ADNP, shares the SxIP motif and shows overlapping neuroprotective activity in vitro. More recently, researchers designed mirror-image variants (D-NAP, SKIP, D-SKIP) to probe the structural requirements for activity and extend half-life. The parent protein ADNP is itself regulated downstream of VIP/PACAP receptor signaling; see the VIP card for the upstream signaling context.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could giving children with ADNP syndrome extra doses of the NAP fragment help reduce cognitive and behavioral symptoms?
If it worked, children with this severe autism-intellectual disability syndrome, which has no approved treatment, might gain an option using a compound already tested for safety in adults.
Could attaching a small targeting molecule to the free end of davunetide guide it into the brain from a simple injection or pill?
If the tagged peptide reaches the brain more efficiently, the same protective effect could be achieved with a lower dose or via a more convenient route, benefiting patients with Alzheimer's disease, traumatic brain injury, or stroke who currently have limited effective treatment options.
Does davunetide's brain-focused activity depend on binding a protein found mostly in neurons?
If confirmed, this would suggest fewer side effects outside the brain, which could make the peptide more attractive for diseases like Alzheimer's or frontotemporal dementia.
Are the two proline residues (at positions 3 and 7) in davunetide important for its low-dose brain protection?
If proline-enforced shape matters, chemists could try building a stable small molecule with the same shape, potentially enabling an oral form where current peptides need nasal or injected delivery.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| ranking score | 0.8215410113334656 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | none_monomer |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-23 |
▸citationbibtex
@peptide{pep10778,
sequence = {NAPVSIPQ},
target = {longevity},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}