Didemnin B
(Synonyms: NSC 325319, NSC 333841) 目录号 : GC49153
A depsipeptide with diverse biological activities
Cas No.:77327-05-0
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
| 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. |
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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. |
|
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].
| 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。 |
||
| 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。
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.PMID:36264623DOI:10.7554/eLife.81608.
Rapid and accurate mRNA translation requires efficient codon-dependent delivery of the correct aminoacyl-tRNA (aa-tRNA) to the ribosomal A site. In mammals, this fidelity-determining reaction is facilitated by the GTPase elongation factor-1 alpha (eEF1A), which escorts aa-tRNA as an eEF1A(GTP)-aa-tRNA ternary complex into the ribosome. 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. Here, we employ single-molecule fluorescence imaging and cryogenic electron microscopy to determine how these natural products inhibit translational elongation on mammalian ribosomes. 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. We also show that Didemnin B and ternatin-4 exhibit distinct effects on the dynamics of aa-tRNA selection that inform on observed disparities in their inhibition efficacies and physiological impacts. These integrated findings underscore the value of dynamics measurements in assessing the mechanism of small-molecule inhibition and highlight potential of single-molecule methods to reveal how distinct natural products differentially impact the human translation mechanism.
Didemnin B. The first marine compound entering clinical trials as an antineoplastic agent
Invest New Drugs 1986;4(3):279-84.PMID:3546184DOI:10.1007/BF00179597.
A new class of marine compounds, the didemnins, with potent antitumor activity has been identified. They share the novel structure of a cyclic depsipeptide. Among three structurally related compounds, Didemnin B is by far the most potent in its in vitro cytotoxicity and in vivo antitumor activity (0.001 microgram/ml inhibits the growth of L1210 leukemia cells by 50%). It also demonstrates good antitumor activity against B16 melanoma and moderate activity against M5076 sarcoma and P388 leukemia. The compound also has good antiviral and potent immunosuppressive properties. Although the precise mechanism of action for the cytotoxicity remains unknown, the agent inhibits protein synthesis more than DNA synthesis and the inhibition of protein synthesis is closely correlated with inhibition of L1210 cell growth. Toxicology studies in CD2F1 mice, Fischer 344 rats and beagle dogs reveal that major target organs are the lymphatics, gastrointestinal tract, liver and kidney. Phase I trials are currently in progress under the auspices of the National Cancer Institute.
Phase II clinical trial of Didemnin B in previously treated small cell lung cancer
Invest New Drugs 1994;12(3):243-9.PMID:7896544DOI:10.1007/BF00873966.
Didemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that Didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for Didemnin B may not be warranted at the stated dose and schedule.
Treatment with Didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice
Physiol Rep 2016 Sep;4(17):e12963.PMID:27613825DOI:10.14814/phy2.12963.
Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, Didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with Didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of Didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with Didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by Didemnin B. These data indicate that 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.
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.PMID:32977024DOI:10.1016/j.phrs.2020.105208.
Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound Didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of Didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of Didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with Didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, Didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, Didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, 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. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.