Davunetide (NAPVSIPQ, NAP) is a microtubule-stabilizing peptide. It interacts with and stabilizes tubulin, thereby compensating for tau loss-of-function in tauopathy models. [1]

Davunetide protected astrocytes against zinc toxicity. [2]
Davunetide promoted neurite outgrowth in PC-12 cells and hippocampal neurons. [2]
Davunetide increased synaptophysin expression in both rat hippocampal and cortical cultures. [2]
Davunetide prevented aggregation of Aβ peptide in vitro. [2]
Davunetide protected against Aβ-induced cellular toxicity in rat cerebral cortex neurons. [2]

In an intranasal davunetide (2 μg/kg) administered once daily for five days a week for sixteen weeks, a diabetic rat model demonstrated protection against problems of the central nervous system [3].

---

In a Drosophila model of tauopathy expressing human tau (htauON3R) in motor neurons, oral administration of Davunetide (NAP) at 2.5 μg/mL significantly improved larval locomotor performance, as measured by body wall contractions per minute, velocity, and meander (P < 0.001, P < 0.0001, P = 0.06, respectively). [1]
NAP treatment (2.5 μg/mL) fully restored microtubule integrity in peripheral axons of htauON3R larvae, as shown by electron microscopy. Untreated htauON3R axons contained 5.32 ± 0.28 correctly aligned microtubule profiles per cross-section, compared to 8.07 ± 0.30 in NAP-treated larvae and 8.10 ± 0.20 in controls. [1]
NAP (2.5 μg/mL) prevented axonal transport disruption in htauON3R larvae, as assessed by vesicular neuropeptide-Y-GFP (vGFP) accumulation. The area of vGFP accumulation was significantly reduced to control levels. NAP also rescued axonal transport deficits when administered after dysfunction had already become established: a 24-hour NAP treatment at day 4 significantly reduced the accumulation area compared to untreated larvae (P < 0.0001). [1]
NAP (2.5 μg/mL) improved neuromuscular junction (NMJ) morphology in htauON3R larvae, restoring tubulin cytoskeleton extension into distal NMJ ends and increasing NMJ area. [1]
NAP did not alter tau phosphorylation at multiple AD-associated epitopes (e.g., AT8, AT180) in htauON3R larvae or adults. Total tau levels were also unchanged. However, NAP increased the percentage of endogenous Drosophila tau (dtau) bound to microtubules without altering htau binding. [1]
NAP treatment did not affect pupariation or eclosion rates in control or htauON3R larvae, indicating low toxicity. [1]

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats (induced by intraperitoneal (ip) injection of streptozotocin (STZ)) [3]
Doses: 2 μg/kg
Route of Administration: Intranasal administration starting the day after STZ injection, Daily dosing, 5 days per week, for 16 weeks
Experimental Results: Impaired spatial memory in diabetic rats was observed in the water maze, manifested by an attenuated learning curve and worsened performance in the probe memory test. Davonidetide treatment Dramatically improved both measures.

---

All experiments were performed in *Drosophila melanogaster*. Expression of htauON3R, htauON4R, and Aβ42;htauON4R was directed to motor neurons using the D42-Gal4 driver or pan-neuronally using Elav-Gal4. Davunetide (NAP) was dissolved in basic fly food at concentrations of 50 ng/mL, 500 ng/mL, 2.5 μg/mL, and 25 μg/mL. Larvae were reared on NAP-containing food from the egg stage (preventive protocol) or transferred to NAP food after 4 days for 1 day (rescue protocol). [1]
Larval locomotion was assessed in wandering third instar larvae on 100 cm² plates for 2 min using Ethovision tracking software. Parameters measured included body wall contractions per minute, velocity, and meander. [1]
For electron microscopy, larval peripheral nerves were dissected, fixed, and processed. Transverse sections were examined, and correctly aligned microtubule profiles were counted. [1]
Axonal transport was assessed using a vGFP reporter expressed in motor neurons. Larvae were imaged, and the total area of vGFP accumulation in peripheral nerves was quantified. [1]
NMJs were stained with anti-horseradish peroxidase (HRP) to visualize presynaptic boutons and anti-tubulin to visualize the cytoskeleton. NMJ area was measured. [1]
Tau phosphorylation and protein levels were assessed by western blot of larval and adult head homogenates using antibodies against total tau and phospho-tau epitopes (AT8, AT180, etc.). [1]

---

All experiments were performed in Drosophila melanogaster. Expression of htauON3R, htauON4R, and Aβ42;htauON4R was directed to motor neurons using the D42-Gal4 driver or pan-neuronally using Elav-Gal4. Davunetide (NAP) was dissolved in basic fly food at concentrations of 50 ng/mL, 500 ng/mL, 2.5 μg/mL, and 25 μg/mL. Larvae were reared on NAP-containing food from the egg stage (preventive protocol) or transferred to NAP food after 4 days for 1 day (rescue protocol). [1]
Larval locomotion was assessed in wandering third instar larvae on 100 cm² plates for 2 min using Ethovision tracking software. Parameters measured included body wall contractions per minute, velocity, and meander. [1]
For electron microscopy, larval peripheral nerves were dissected, fixed, and processed. Transverse sections were examined, and correctly aligned microtubule profiles were counted. [1]
Axonal transport was assessed using a vGFP reporter expressed in motor neurons. Larvae were imaged, and the total area of vGFP accumulation in peripheral nerves was quantified. [1]
NMJs were stained with anti-horseradish peroxidase (HRP) to visualize presynaptic boutons and anti-tubulin to visualize the cytoskeleton. NMJ area was measured. [1]
Tau phosphorylation and protein levels were assessed by western blot of larval and adult head homogenates using antibodies against total tau and phospho-tau epitopes (AT8, AT180, etc.). [1]

Davunetide (NAP) penetrates the blood-brain barrier (BBB) and is non-toxic. [1]

Davunetide (NAP) did not affect pupariation or eclosion rates in control or htauON3R Drosophila larvae, indicating low toxicity at the tested concentrations. [1]

[1]. NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. Mol Psychiatry. 2013;18(7):834-842.

[2]. Davunetide improves spatial learning and memory in Alzheimer's disease-associated rats. Physiol Behav. 2017;174:67-73.

[3]. Davunetide (NAP) as a preventative treatment for central nervous system complications in a diabetes rat model. Neurobiol Dis. 2011;44(3):327-339.

Davinetide is an oligopeptide. Davinetide has been used in clinical trials to treat progressive non-fluent aphasia, progressive supranuclear palsy, predictive tau proteinosis (including corticobasal degeneration syndrome), and frontotemporal dementia associated with Parkinson's syndrome related to chromosome 17. Davinetide is the first drug to improve memory function by influencing the mechanisms that cause physical damage to neurofibrillary tangles in the brain. Neurofibrillary tangles are one of two known pathological markers of amnesic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Davinetide is derived from a naturally occurring neuroprotective brain protein called activity-dependent neuroprotective protein. Mechanism of Action: Davinetide interacts with microtubules to 1) prevent the formation of neurofibrillary tangles, protecting the microtubule network from "death signals"; and 2) repair the microtubule network if the brain cell death process has already begun. The repair of the microtubule network explains the improved cognitive abilities in treated animals compared to the untreated group.

---

Davunetide (NAP, NAPVSIPQ) is a small octapeptide derived from activity-dependent neuroprotective protein (ADNP). It stabilizes microtubules and has been shown to penetrate the blood-brain barrier with low toxicity. In this study, NAP prevented and rescued tau-mediated neuronal dysfunction (including microtubule destabilization, axonal transport disruption, synaptic defects, and behavioral impairments) in a Drosophila model of tauopathy without altering tau phosphorylation or total tau levels. The mechanism involves by-passing abnormal tau and directly stabilizing microtubules. NAP has been investigated in clinical trials for progressive supranuclear palsy and amnestic mild cognitive impairment. [1]

C36H60N10O12

824.93

824.439

211439-12-2

211439-12-2;

9832404

White to off-white solid powder

1.3±0.1 g/cm3

1333.8±65.0 °C at 760 mmHg

760.5±34.3 °C

0.0±0.6 mmHg at 25°C

1.566

-1.78

10

13

22

58

1560

9

CC[C@@H]([C@H](NC([C@@H](NC([C@@H](NC([C@@H]1CCCN1C([C@@H](NC([C@@H](N)CC(N)=O)=O)C)=O)=O)C(C)C)=O)CO)=O)C(N2CCC[C@H]2C(N[C@H](C(O)=O)CCC(N)=O)=O)=O)C

DWLTUUXCVGVRAV-XWRHUKJGSA-N

InChI=1S/C36H60N10O12/c1-6-18(4)28(35(56)46-14-8-9-23(46)31(52)41-21(36(57)58)11-12-25(38)48)44-30(51)22(16-47)42-33(54)27(17(2)3)43-32(53)24-10-7-13-45(24)34(55)19(5)40-29(50)20(37)15-26(39)49/h17-24,27-28,47H,6-16,37H2,1-5H3,(H2,38,48)(H2,39,49)(H,40,50)(H,41,52)(H,42,54)(H,43,53)(H,44,51)(H,57,58)/t18-,19-,20-,21-,22-,23-,24-,27-,28-/m0/s1

(2S)-5-amino-2-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoic acid

Davunetide AL 208 AL 108

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~151.53 mM)
H2O : ~100 mg/mL (~121.22 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)