Didemnin B
(Synonyms: NSC 325319, NSC 333841) 目录号 : GC49153
Didemnin B 是一种由海洋被囊类动物产生的环状肽肽，可特异性结合 EEF1A 的 GTP 结合构象，抑制其从核糖体 A 位点释放并防止随后的肽延伸。
Cas No.:77327-05-0
Sample solution is provided at 25 µL, 10mM.
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Didemnin B is a cyclic depsipeptide produced by marine tunicates that specifically binds the GTP-bound conformation of EEF1A, inhibiting its release from the ribosomal A site and preventing subsequent peptide elongation.Didemnin B thereby specifically inhibits eEF1A-1 release from the ribosomal A-site, preventing peptidyl-tRNA translocation and subsequent peptide elongation. It is a potential anticancer, antiviral, and immunosuppressive agent[1,2].
Didemnin B (80 nM,48h) prevent upregulation of GRP78 protein in HepG2 cells,in association with sustained inhibition of protein synthesis[3]. The structurally unrelated cyclic peptides didemnin B and ternatin-4 bind to the eEF1A(GTP)-aa-tRNA ternary complex and inhibit translation but have different effects on protein synthesis in vitro and in vivo. By binding to a common site on eEF1A, didemnin B and ternatin-4 trap eEF1A in an intermediate state of aa-tRNA selection, preventing eEF1A release and aa-tRNA accommodation on the ribosome[5]. Didemnin B can induce apoptosis in a wide range of transformed cell lines[6].
Acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease[4].Didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver[7].
References:
[1]. Marco E, Martín-Santamaría S, et,al. Structural basis for the binding of didemnins to human elongation factor eEF1A and rationale for the potent antitumor activity of these marine natural products. J Med Chem. 2004 Aug 26;47(18):4439-52. doi: 10.1021/jm0306428. PMID: 15317456.
[2]. Lee J, Currano JN, et,al. Didemnins, tamandarins and related natural products. Nat Prod Rep. 2012 Mar;29(3):404-24. doi: 10.1039/c2np00065b. Epub 2012 Jan 23. PMID: 22270031.
[3]. Stoianov AM, Robson DL, et,al. Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. PLoS One. 2015 Jun 23;10(6):e0131269. doi: 10.1371/journal.pone.0131269. PMID: 26102086; PMCID: PMC4478042.
[4]. Hetherington AM, Sawyez CG, et,al. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice. Physiol Rep. 2016 Sep;4(17):e12963. doi: 10.14814/phy2.12963. PMID: 27613825; PMCID: PMC5027364.
[5]. Juette MF, Carelli JD, et,al. Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes. Elife. 2022 Oct 20;11:e81608. doi: 10.7554/eLife.81608. PMID: 36264623; PMCID: PMC9584604.
[6]. Baker MA, Grubb DR, et,al. Didemnin B induces apoptosis in proliferating but not resting peripheral blood mononuclear cells. Apoptosis. 2002 Oct;7(5):407-12. doi: 10.1023/a:1020078907108. PMID: 12207173.
[7]. Wilson RB, Chen YJ, et,al.The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease. Pharmacol Res. 2020 Nov;161:105208. doi: 10.1016/j.phrs.2020.105208. Epub 2020 Sep 22. PMID: 32977024.
Didemnin B 是一种由海洋被囊类动物产生的环状肽肽，可特异性结合 EEF1A 的 GTP 结合构象，抑制其从核糖体 A 位点释放并防止随后的肽延伸。Didemnin B 从而特异性抑制 eEF1A-1 从核糖体释放A 位点，防止肽基-tRNA 易位和随后的肽延伸。它是一种潜在的抗癌剂、抗病毒剂和免疫抑制剂[1,2]。
Didemnin B (80 nM,48h) 阻止 HepG2 细胞中 GRP78 蛋白的上调，并持续抑制蛋白质合成[3]。结构无关的环肽 didemnin B 和 ternatin-4 与 eEF1A(GTP)-aa-tRNA 三元复合物结合并抑制翻译，但在体外和体内对蛋白质合成有不同的影响。通过与 eEF1A 上的共同位点结合，didemnin B 和 ternatin-4 将 eEF1A 捕获在 aa-tRNA 选择的中间状态，从而阻止 eEF1A 释放和 aa-tRNA 在核糖体上的调节[5]。 Didemnin B 可在多种转化细胞系中诱导细胞凋亡[6]。
用 EEF1A 抑制剂 didemnin B 进行急性干预，可通过不完全依赖于食物摄入量减少的机制改善患有 NAFLD 的肥胖小鼠的肝脏脂毒性，表明这种 ER 应激相关疾病的潜在治疗策略[4]< /sup>.Didemnin B 改善肥胖患者的肝脂肪变性、葡萄糖耐量和血脂，与适度的、可能是激素性的、参与肝脏细胞应激反应和能量平衡的通路上调有关[7].
| Molecular Dynamics of the Ternary Complexes eEF1A·GTP·Mg2+ and Didemnin B·eEF1A·GTP·Mg2+ [1]: | |
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Preparation Method |
The eEF1A·GTP·Mg2+ and Didemnin B·eEF1A·GTP·Mg2+ complexes were solvated by adding a spherical shell of ∼3000 TIP3P water molecules centered at CG1 of Leu77. The radius of this water shell was 35 Å to ensure the solvation of the interdomain cleft in both complexes. These water molecules were first energy-minimized, and then both waters and all protein residues were allowed to relax. In each case, 1000 steps of steepest descent were followed by 2000 steps of conjugate gradient energy minimization. The final coordinate sets were used as input for the subsequent MD simulations. SHAKE was used for all bonds, and the integration time step was 2 fs. Only the water molecules were free to move for the first 100 ps. For the remaining 2000 ps the whole system was allowed to relax. |
|
Applications |
Didemnin B specifically binds GTP-bound eEF1A-1, in a location between the aa-tRNA-binding and GTP-binding domains, but distinct from the actin-binding domain. Didemnin B thereby specifically inhibits eEF1A-1 release from the ribosomal A-site, preventing peptidyl-tRNA translocation and subsequent peptide elongation. |
| Cell experiment [2]: | |
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Cell lines |
HepG2 cells |
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Preparation Method |
Cells were treated with palmitate, with or without 80 nM didemnin B, followed by assessment of ER stress (6 h), protein synthesis (6-24 h), and cell death (48 h). |
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Reaction Conditions |
80 nM didemnin B for 6-48 h |
|
Applications |
Didemnin B prevent upregulation of GRP78 protein in HepG2 cells，in association with sustained inhibition of protein synthesis. |
| Animal experiment [3]: | |
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Animal models |
Five-week-old male C57BL/6J and leptin-deficient (ob/ob) mice on a C57BL/6J background |
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Preparation Method |
Used 5-week-old male C57BL/6J (lean control) and leptin-deficient ob/ob mice. All mice were fed AIN-76A diet for 4 weeks. During week 5, mice were given i.p. injections of didemnin B (50 μg/kg) or vehicle control on days 1, 4, and 7. |
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Dosage form |
didemnin B (50 μg/kg) on days 1, 4, and 7( i.p. injections) |
|
Applications |
Didemnin B treatment modestly reduces food consumption in obese mice. |
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References: [1]. Marco E, Martín-Santamaría S, et,al. Structural basis for the binding of didemnins to human elongation factor eEF1A and rationale for the potent antitumor activity of these marine natural products. J Med Chem. 2004 Aug 26;47(18):4439-52. doi: 10.1021/jm0306428. PMID: 15317456. [2]. Stoianov AM, Robson DL, et,al. Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. PLoS One. 2015 Jun 23;10(6):e0131269. doi: 10.1371/journal.pone.0131269. PMID: 26102086; PMCID: PMC4478042. [3]. Hetherington AM, Sawyez CG, et,al.Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice. Physiol Rep. 2016 Sep;4(17):e12963. doi: 10.14814/phy2.12963. PMID: 27613825; PMCID: PMC5027364. |
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| Cas No. | 77327-05-0 | SDF | |
| 别名 | NSC 325319, NSC 333841 | ||
| Canonical SMILES | O=C1N2[C@](CCC2)([H])C(N([C@H](C(O[C@@H]([C@@H](C(N[C@]([C@H](CC(O[C@H](C([C@@H](C(N[C@H]1CC(C)C)=O)C)=O)C(C)C)=O)O)([H])[C@@H](C)CC)=O)NC([C@@H](CC(C)C)N(C)C([C@H]3N(C([C@@H](O)C)=O)CCC3)=O)=O)C)=O)CC4=CC=C(C=C4)OC)C)=O | ||
| 分子式 | C57H89N7O15 | 分子量 | 1112.4 |
| 溶解度 | Acetonitrile: 1 mg/ml | 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 | 0.899 mL | 4.4948 mL | 8.9896 mL |
| 5 mM | 0.1798 mL | 0.899 mL | 1.7979 mL |
| 10 mM | 0.0899 mL | 0.4495 mL | 0.899 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。
Quality Control & SDS
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- Purity: >98.00%
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