Dihexa (PNB-0408)
(Synonyms: 益智二肽) 目录号 : GC30768
Dihexa (PNB-0408) (N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide) is an oral active, blood-brain barrier-permeable angiotensin IV analogue.
Cas No.:1401708-83-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Human embryonic kidney (HEK)-293 cells |
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Preparation Method |
Cells were seeded in six-well tissue culture plates. The cells were serum-deprived for 24 hours prior to the treatment to reduce the basal levels of phospho-Met. Following serum starvation, cocktails composed of vehicle and HGF with/without Dihexa (PNB-0408) or Nle1 -AngIV were prepared and preincubated for 30 minutes at room temperature. The cocktail was then added to the cells for 10 minutes to stimulate the Met receptor activation. Cells were harvested using radio immunoprecipitation assay lysis buffer supplemented with phosphatase inhibitor cocktails 1 and 2. |
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Reaction Conditions |
10-10 M and 10-12 M;30 minutes; room temperature |
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Applications |
Dihexa (PNB-0408) at both concentrations(10-10 M and 10-12 M) markedly augmented the capacity of HGF to activate c-Met. |
| Animal experiment [2]: | |
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Animal models |
Male (APP/PS1) mice and wild-type (C57) mice |
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Preparation Method |
The experiment was divided into two parts: Part 1, in which they were randomly divided into four groups: the WT group, the APP/PS1 group, the APP/PS1+ Dihexa (PNB-0408) (1.44 mg/kg) group, and the APP/PS1+ Dihexa (2.88 mg/kg) group, and Part 2, in which mice were divided into three groups: the APP/PS1 group, the Dihexa (2.88 mg/kg) group, and the Dihexa (2.88 mg/kg) + wortmannin group. Dihexa and wortmannin were dissolved in 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, and administered intragastrically to the APP/PS1 mice. The Dihexa was administered intraperitoneally to the APP/PS1 mice from six to nine months old. Additionally, 0.9% saline was administered to the WT group once daily for three months. |
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Dosage form |
1.44/2.88 mg/kg, i.g., for 3 months; 1.44/2.88 mg/kg, i.p., for 5 days. |
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Applications |
Dihexa (PNB-0408) restored AngIV decline in APP/PS1 mice, saved the cognitive function of mice, improved neuronal loss in mice and reduced neuroinflammation and inhibited glial activation in the mouse brain. |
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References: [1]. Benoist CC, Kawas LH, et,al.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3. PMID: 25187433; PMCID: PMC4201273. |
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Dihexa (PNB-0408) (N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide) is an oral active, blood-brain barrier-permeable angiotensin IV analogue. Dihexa (PNB-0408) is a synthetically derived Angiotensin IV analog that is blood-brain barrier permeable, stable, and orally bioavailable[1].
Under Dihexa (PNB-0408) stimulation, the hepatocyte growth factor (HGF)/c-Met receptor system can induce dendritic dendrites and synaptogenesis[2]. The hepatoblasts were differentiated into HLCs by Dihexa and dexamethasone[3]. Dihexa(PNB-0408)( 0.1 μM) combining Vitamin C, and Forskolin (VDF) could substitute growth factors to induce hepatic specification[4]. Dihexa (PNB-0408) at both concentrations(10-10 M and 10-12 M; 30 minutes; room temperature) markedly augmented the capacity of HGF to activate c-Met[5].
Dihexa (PNB-0408) (1.44/2.88 mg/kg ;i.g.; 3 months) restored AngIV decline in APP/PS1 mice, saved the cognitive function of mice, improved neuronal loss in mice and reduced neuroinflammation and inhibited glial activation in the mouse brain[6]. Dihexa (PNB-0408)(10-6M-10-13M;30 min) protects lateral line hair cells from aminoglycoside ototoxicity. Dihexa does not alter the entry of aminoglycosides into hair cells but rather attenuates cell death through an HGF-dependent signaling mechanism [7]. Dihexa (PNB-0408) (2-4mg/kg;b.wt.;16 weeks) is promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation[8].
References:
[1]. McCoy AT, Benoist CC, et,al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. doi: 10.1124/jpet.112.199497. Epub 2012 Oct 10. PMID: 23055539; PMCID: PMC3533412.
[2]. Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. doi: 10.3233/JAD-142814. PMID: 25649658.
[3]. Mathapati S, Siller R, et,al. Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2016 Aug 17;38:1G.6.1-1G.6.18. doi: 10.1002/cpsc.13. PMID: 27532814.
[4]. Pan T, Wang N, et,al. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem Cell Res Ther. 2022 Apr 11;13(1):159. doi: 10.1186/s13287-022-02831-1. PMID: 35410439; PMCID: PMC8996222.
[5]. Benoist CC, Kawas LH, et,al.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3. PMID: 25187433; PMCID: PMC4201273.
[6]. Sun X, Deng Y,et,al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021 Nov 11;11(11):1487. doi: 10.3390/brainsci11111487. PMID: 34827486; PMCID: PMC8615599.
[7]. Uribe PM, Kawas LH, et,al. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015 Jan 28;9:3. doi: 10.3389/fncel.2015.00003. PMID: 25674052; PMCID: PMC4309183.
[8]: Weiss JB, Phillips CJ, et,al.Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond). 2021 Oct 8;71:102917. doi: 10.1016/j.amsu.2021.102917. PMID: 34703584; PMCID: PMC8524106.
Dihexa (PNB-0408)（N-己酸-Tyr-Ile-(6)-氨基己酰胺）是一种具有口服活性、可透过血脑屏障的血管紧张素 IV 类似物。 Dihexa (PNB-0408) 是一种合成衍生的血管紧张素 IV 类似物，具有血脑屏障渗透性、稳定性和口服生物利用度[1]。
在 Dihexa (PNB-0408) 刺激下，肝细胞生长因子 (HGF)/c-Met 受体系统可诱导树突状树突和突触发生[2]。 Dihexa和地塞米松[3]将成肝细胞分化为HLCs。 Dihexa(PNB-0408)( 0.1 μM) 结合维生素 C 和 Forskolin (VDF) 可以替代生长因子诱导肝脏规范化[4]。 Dihexa (PNB-0408) 在两个浓度（10-10 M 和 10-12 M；30 分钟；室温）下显着增强 HGF 激活 c-Met[5] 的能力。\n
Dihexa (PNB-0408)（1.44/2.88 mg/kg ；i.g.；3 个月）恢复 APP/PS1 小鼠的 AngIV 下降，挽救小鼠的认知功能，改善小鼠的神经元丢失并减少神经炎症并抑制神经胶质细胞激活在小鼠大脑中[6]。 Dihexa (PNB-0408)（10-6M-10-13M；30 分钟）保护侧线毛细胞免受氨基糖苷类的耳毒性。 Dihexa 不会改变氨基糖苷类药物进入毛细胞，而是通过 HGF 依赖性信号机制[7] 减弱细胞死亡。 Dihexa (PNB-0408)（2-4mg/kg；b.wt.；16 周）有望成为辅助疗法的候选药物，以促进手术神经修复后的肢体功能恢复，并对周围神经损伤和肢体移植有影响 [8].
| Cas No. | 1401708-83-5 | SDF | |
| 别名 | 益智二肽 | ||
| Canonical SMILES | OC1=CC=C(C[C@H](NC(CCCCC)=O)C(N[C@H](C(NCCCCCC(N)=O)=O)[C@@H](C)CC)=O)C=C1 | ||
| 分子式 | C27H44N4O5 | 分子量 | 504.66 |
| 溶解度 | DMSO : ≥ 30 mg/mL (59.45 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9815 mL | 9.9077 mL | 19.8153 mL |
| 5 mM | 0.3963 mL | 1.9815 mL | 3.9631 mL |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9815 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure
Loss of sensory hair cells from exposure to certain licit drugs (e.g., aminoglycoside antibiotics, platinum-based chemotherapy agents) can result in permanent hearing loss. Here we ask if allosteric activation of the hepatocyte growth factor (HGF) cascade via Dihexa, a small molecule drug candidate, can protect hair cells from aminoglycoside toxicity. Unlike native HGF, Dihexa is chemically stable and blood-brain barrier permeable. As a synthetic HGF mimetic, it forms a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades. To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins. A dose-response relationship for Dihexa protection was established using two ototoxins, neomycin and gentamicin. We found that a Dihexa concentration of 1 μM confers optimal protection from acute treatment with either ototoxin. Pretreatment with Dihexa does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating that Dihexa's protection is likely mediated by intracellular events and not by inhibiting aminoglycoside entry. Dihexa-mediated protection is attenuated by co-treatment with the HGF antagonist 6-AH, further evidence that HGF activation is a component of the observed protection. Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK. Addition of an amino group to the N-terminal of Dihexa also attenuates the protective response, suggesting that even small substitutions greatly alter the specificity of Dihexa for its target. Our data suggest that Dihexa confers protection of hair cells through an HGF-mediated mechanism and that Dihexa holds clinical potential for mitigating chemical ototoxicity.
Dimeric DOTA-alpha-melanocyte-stimulating hormone analogs: synthesis and in vivo characteristics of radiopeptides with high in vitro activity
Dimeric analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) labeled with radiometals are potential candidates for diagnosis and therapy of melanoma by receptor-mediated tumor targeting. Both melanotic and amelanotic melanomas (over-)express the melanocortin-1 receptor (MC1-R), the target for alpha-MSH. In the past, dimerized MSH analogs have been shown to display increased receptor affinity compared to monomeric MSH, offering the possibility of improving the ratio between specific uptake of radiolabeled alpha-MSH by melanoma and nonspecific uptake by the kidneys. We have designed three linear dimeric analogs containing a slightly modified MSH hexapeptide core sequence (Nle-Asp-His-d-Phe-Arg-Trp) in parallel or antiparallel orientation, a short spacer, and the DOTA chelator for incorporation of the radiometal. In vitro, all three peptides were more potent ligands of the mouse B16-F1 melanoma cell melanocortin-1 receptor (MC1-R) than DOTA-NAPamide, which served as standard. The binding activity of DOTA-diHexa(NC-NC)-amide was 1.75-fold higher, that of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was 3.37-fold higher, and that of DOTA-diHexa(CN-NC)-amide was 2.34-fold higher. Using human HBL melanoma cells, the binding activity of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was sixfold higher than that of DOTA-NAPamide. Uptake by cultured B16-F1 cells was rapid and almost quantitative. In vivo, however, the data were less promising: tumor-to-kidney ratios 4 hr postinjection were 0.11 for [(111)In]DOTA-diHexa(NC-NC)-amide, 0.26 for diHexa(NC-NC)-Gly-Lys([(111)In]DOTA)-amide, and 0.36 for [(111)In]DOTA-diHexa(CN-NC)-amide, compared to 1.67 for [(111)In]DOTA-NAPamide. It appears that despite the higher affinity to the MC1-R of the peptide dimers and their excellent internalization in vitro, the uptake by melanoma tumors in vivo was lower, possibly because of reduced tissue penetration. More striking, however, was the marked increase of kidney uptake of the dimers, explaining the unfavorable ratios. In conclusion, although radiolabeled alpha-MSH dimer peptides display excellent receptor affinity and internalization, they are no alternative to the monomeric DOTA-NAPamide for in vivo application.
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system
A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier-penetrant analogs, and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, blood-brain barrier-permeable analog N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa). Therefore, the goal of this study was to elucidate the mechanism that underlies dihexa's procognitive activity. Here, we demonstrate that dihexa binds with high affinity to hepatocyte growth factor (HGF) and both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle(1)-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a short hairpin RNA directed at c-Met. Most importantly, the procognitive/antidementia capacity of orally delivered dihexa was blocked by an HGF antagonist delivered intracerebroventricularly as measured using the Morris water maze task of spatial learning.
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway
The renin-angiotensin system (RAS) is a paracrine RAS within the central nervous system (CNS) and is closely related to Alzheimer's disease (AD). The endogenous hexapeptide angiotensin IV (Ang IV), an important component of the brain RAS, was found to rescue cognitive impairment and recover memory in previous studies. In our study, we used different doses of Dihexa, which can be orally administered and cross the BBB in APP/PS1 mice. We found that the amount of AngIV in mouse tissue increased after the administration of Dihexa compared to that in the WT group. Meanwhile, Dihexa restored spatial learning and cognitive functions in the Morris water maze test. Dihexa increased the neuronal cells and the expression of SYP protein in APP/PS1 mice in Nissl staining. Furthermore, Dihexa decreased the activation of astrocytes and microglia, markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-10. Dihexa activated the PI3K/AKT signaling pathway, while PI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of APP/PS1 mice. These findings highlight the brain AngIV/PI3K/AKT axis as a potential target for the treatment of AD.
Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells
Hepatocyte-like cells (HLCs) generated in vitro from human pluripotent stem cells (hPSCs) provide an invaluable resource for basic research, regenerative medicine, drug screening, toxicology, and modeling of liver disease and development. This unit describes a small-molecule-driven protocol for in vitro differentiation of hPSCs into HLCs without the use of growth factors. hPSCs are coaxed through a developmentally relevant route via the primitive streak to definitive endoderm (DE) using the small molecule CHIR99021 (a Wnt agonist), replacing the conventional growth factors Wnt3A and activin A. The small-molecule-derived DE is then differentiated to hepatoblast-like cells in the presence of dimethyl sulfoxide. The resulting hepatoblasts are then differentiated to HLCs with N-hexanoic-Tyr, Ile-6 aminohexanoic amide (Dihexa, a hepatocyte growth factor agonist) and dexamethasone. The protocol provides an efficient and reproducible procedure for differentiation of hPSCs into HLCs utilizing small molecules. ? 2016 by John Wiley & Sons, Inc.