RR-11a
目录号 : GC33063
RR-11a是人工合成的天冬酰胺酰内肽酶Legumain抑制剂。
Cas No.:1361390-56-8
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
Animal experiment: | Mice[1]Mice bearing 4T1 orthothopic tumors of approximately 500 mm3 are injected once intravenously with RR-11a+ or RR-11a-nanoparticles labeled with rhodamine B. Alternatively, mice are injected intravenously 3 times at 48-hour intervals with RDZ-218, NP-DOX, free DOX, or saline. Twenty-four hours after the final treatment, animals are sacrificed and spleen, kidney, lungs, liver, heart and tumor are collected, frozen in OCT compound, immediately sectioned and imaged by fluorescence microscopy[1]. |
References: [1]. Liao D, et al. Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity. Nanomedicine. 2011 Dec;7(6):665-73. | |
RR-11a is a synthetic enzyme inhibitor of Legumain.
Legumain-targeted RR-11a-coupled nanoparticles reveal high ligand-receptor affinity, enhance solid-tumor penetration and uptake by tumor cells[1].
Treatment of tumor-bearing mice with RR-11a-coupled NPs encapsulating doxorubicin results in improved tumor selectivity and drug sensitivity, leading to complete inhibition of tumor growth[1].
[1]. Liao D, et al. Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity. Nanomedicine. 2011 Dec;7(6):665-73.
| Cas No. | 1361390-56-8 | SDF | |
| Canonical SMILES | O=C(N[C@@H](C)C(N[C@@H](C)C(NN(CC(N)=O)C(/C=C/C(ON1C(CCC1=O)=O)=O)=O)=O)=O)OCC2=CC=CC=C2 | ||
| 分子式 | C24H28N6O10 | 分子量 | 560.51 |
| 溶解度 | Soluble in DMSO | 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 | 1.7841 mL | 8.9204 mL | 17.8409 mL |
| 5 mM | 0.3568 mL | 1.7841 mL | 3.5682 mL |
| 10 mM | 0.1784 mL | 0.892 mL | 1.7841 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。
Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI
Cell Death Dis 2021 Jan 11;12(1):65.PMID:33431801DOI:10.1038/s41419-020-03362-4.
Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H2DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.
Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-β Deposition in an Alzheimer's Disease Model
Acta Biomater 2022 Mar 15;141:388-397.PMID:35045359DOI:10.1016/j.actbio.2022.01.023.
Inhibition of asparagine endopeptidase (AEP) has been implied to be effective for treating tau- and amyloid-beta-mediated neurodegenerative diseases, although a method for targeted intracerebral delivery of AEP inhibitors has not yet been achieved. Here, we fabricated ultrasound-responsive nanobubbles (NBs) to load AEP inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD, i.e. NB(11a)-A and NB(11a)-R, for AEP-targeted treatment of Alzheimer's disease (AD). The developed NBs were uniform, small in size (50.1 ± 1.5 nm), with strong echogenicity and high drug loading efficiency (∼91.97%). When intravenously co-injected in the APP/PS1 mouse model, NB(11a)-R could adhere to endothelial cells and enhance transient opening of the blood-brain barrier (BBB) upon focused ultrasound oscillations, allowing the rest NBs/localized released RR-11a molecules to enter the brain, and then NB(11a)-A could selectively bind with the impaired neurons and deposit RR-11a molecules at the AD lesion. As a result, co-administration of NB(11a)-A and NB(11a)-R significantly promoted accumulation of RR-11a in the mouse brain, and substantially alleviated both tau cleavage and amyloid plaques deposition in the hippocampus. Most strikingly, the cognitive ability of the AD model mice was dramatically improved, achieving a level close to the normal mice. Overall, this unique AEP-targeted nanobubble design provides an efficient intracerebral drug delivery strategy and significantly enhances treatment efficacy of AD. STATEMENT OF SIGNIFICANCE: Asparagine endopeptidase (AEP) is an innovative therapeutic target simultaneously involved in Aβ and tau-mediated Alzheimer's disease (AD) pathology, but targeted delivery of AEP inhibitors has not been achieved yet. Here we developed an efficient strategy to deliver AEP inhibitor RR-11a towards impaired neurons. We fabricated RR-11a-loaded ultrasound-responsive nanobubbles (NBs) and modified the NB surface with RGD peptide to promote BBB crossing upon focused ultrasound oscillations, or with AAN peptide to increase binding of NBs on the neurons. Our results indicated that, co-administration of the NB(11a)-A and NB(11a)-R significantly enhanced accumulation of RR-11a molecules at the AD lesion, alleviated both tau cleavage and amyloid plaques deposition in the hippocampus, and consequently restored cognitive function of the AD model mice.
Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity
Nanomedicine 2011 Dec;7(6):665-73.PMID:21419870DOI:10.1016/j.nano.2011.03.001.
Unresolved problems associated with ligand-targeting of liposomal nanoparticles (NPs) to solid tumors include variable target receptor expression due to genetic heterogeneity and insufficient target specificity, leading to systemic toxicities. This study addresses these issues by developing a novel ligand-targeting strategy for liposomal NPs using RR-11a, a synthetic enzyme inhibitor of Legumain, an asparaginyl endopeptidase. Cell-surface expression of Legumain is driven by hypoxic stress, a hallmark of solid tumors. Legumain-targeted RR-11a-coupled NPs revealed high ligand-receptor affinity, enhanced solid-tumor penetration and uptake by tumor cells. Treatment of tumor-bearing mice with RR-11a-coupled NPs encapsulating doxorubicin resulted in improved tumor selectivity and drug sensitivity, leading to complete inhibition of tumor growth. These antitumor effects were achieved while eliminating systemic drug toxicity. Therefore, synthetic enzyme inhibitors, such as RR-11a, represent a new class of compounds that can be used for highly specific ligand-targeting of NPs to solid tumors. From the clinical editor: This study addresses the problems associated with ligand-targeting of liposomal nanoparticles to solid tumors with variable target receptor expression. A novel and efficacious targeting strategy has been developed towards a synthetic enzyme inhibitor of Legumain. The authors demonstrate successful tumor growth inhibiting effect while eliminating systemic drug toxicity in an animal model using this strategy.
Legumain promotes fibrogenesis in chronic pancreatitis via activation of transforming growth factor β1
J Mol Med (Berl) 2020 Jun;98(6):863-874.PMID:32415356DOI:10.1007/s00109-020-01911-0.
Chronic pancreatitis (CP) is a major risk factor for pancreatic cancer; however, little is known about the pathogenic mechanisms underlying the development of CP. Legumain (Lgmn) has been linked to some chronic inflammatory diseases. The present study investigated the role of legumain in pancreatic fibrogenesis. We induced CP in wild type C57BL6 (WT), Lgmn-deficient (Lgmn-/-), Lgmnflox/flox and Lgmnflox/flox × LysMCre mice by intraperitoneal injection of caerulein for 4 weeks. Pancreata were collected and analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and histology. Pancreatic stellate cells and macrophages were isolated and studied using immunofluorescence, gelatin zymography, and enzyme-linked immunosorbent assay. The effects of inhibition of legumain were investigated in vivo by administration of the specific legumain inhibitor, RR-11a. Legumain was found to be upregulated in the serum and pancreatic tissues of mice with caerulein-induced CP. Mice with global and macrophage-specific legumain deficiency exhibited significantly reduced development of pancreatic fibrosis compared with control mice, based on pancreas size, histology, and expression of fibrosis-associated genes. Our results indicate that legumain promotes activation of pancreatic stellate cells and increases synthesis of extracellular matrix proteins via activation of matrix metalloproteinase-2(MMP-2), which hydrolyzes the transforming growth factor-β1 (TGF-β1) precursor to form active TGF-β1. Administration of RR-11a markedly attenuated pancreatic fibrosis in mice with CP. Deficiency or inhibition of legumain significantly reduces the severity of pancreatic fibrosis by suppressing activation of the TGF-β1 precursor. Our results highlight the potential of legumain as a novel therapeutic target for CP. KEY MESSAGES: • Legumain expression was markedly upregulated in CP mice. • Deletion of legumain attenuated pancreatic fibrosis in CP mice. • Legumain promotes fibrosis via MMP-2 activation, which hydrolyzed the TGF-β1 precursor to the active form. • Legumain is a potential therapeutic target for the management of CP.
Legumain is a predictor of all-cause mortality and potential therapeutic target in acute myocardial infarction
Cell Death Dis 2020 Nov 26;11(11):1014.PMID:33243972DOI:10.1038/s41419-020-03211-4.
The prognostic impact of extracellular matrix (ECM) modulation and its regulatory mechanism post-acute myocardial infarction (AMI), require further clarification. Herein, we explore the predictive role of legumain-which showed the ability in ECM degradation-in an AMI patient cohort and investigate the underlying mechanisms. A total of 212 AMI patients and 323 healthy controls were enrolled in the study. Moreover, AMI was induced in mice by permanent ligation of the left anterior descending artery and fibroblasts were adopted for mechanism analysis. Based on the cut-off value for the receiver-operating characteristics curve, AMI patients were stratified into low (n = 168) and high (n = 44) plasma legumain concentration (PLG) groups. However, PLG was significantly higher in AMI patients than that in the healthy controls (median 5.9 μg/L [interquartile range: 4.2-9.3 μg/L] vs. median 4.4 μg/L [interquartile range: 3.2-6.1 μg/L], P < 0.001). All-cause mortality was significantly higher in the high PLG group compared to that in the low PLG group (median follow-up period, 39.2 months; 31.8% vs. 12.5%; P = 0.002). Multivariate Cox regression analysis showed that high PLG was associated with increased all-cause mortality after adjusting for clinical confounders (HR = 3.1, 95% confidence interval (CI) = 1.4-7.0, P = 0.005). In accordance with the clinical observations, legumain concentration was also increased in peripheral blood, and infarcted cardiac tissue from experimental AMI mice. Pharmacological blockade of legumain with RR-11a, improved cardiac function, decreased cardiac rupture rate, and attenuated left chamber dilation and wall thinning post-AMI. Hence, plasma legumain concentration is of prognostic value in AMI patients. Moreover, legumain aggravates cardiac remodelling through promoting ECM degradation which occurs, at least partially, via activation of the MMP-2 pathway.