SRI-41315
目录号 : GC69942SRI-41315是一种有效的eRF1降解剂。
Cas No.:1613509-49-1
Sample solution is provided at 25 µL, 10mM.
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SRI-41315 is a potent eRF1 degrading agent[1]. eRF1 (eukaryotic release factor 1) is a translation termination factor in eukaryotes, primarily responsible for recognizing stop codons (UAA, UAG, and UGA) and catalyzing the release of the nascent peptide chain from the ribosome, thereby terminating protein synthesis[2]. SRI-41315 acts as a molecular glue in the ribosomal decoding center, inducing a tight binding of eRF1 to the ribosome, which increases the recognition of cryptic stop codons and triggers the degradation of eRF1[3]. This mechanism leads to reduced translation termination and promotes readthrough of premature stop codons (PTC), restoring the full-length expression of truncated proteins caused by PTCs[4]. SRI-41315 is commonly used in the study of genetic diseases caused by PTCs, such as fibrosis and Hurler syndrome (mucopolysaccharidosis type I, MPS I)[5-7].
In vitro, treatment of human bronchial epithelial cells with SRI-41315 (5μM; 24h) induces a prolonged pause at stop codons, suppresses PTCs associated with cystic fibrosis, restores CFTR expression and function, reduces eRF1 abundance, and potentiates aminoglycoside-mediated readthrough to synergistically increase CFTR activity[1].
In vivo, oral administration of Hurler rats with SRI-41315 (40mg/kg/day; 14 days) promotes readthrough of premature termination codons by triggering eRF1 degradation by a ribosome-associated quality control pathway involving GCN1, RNF14, and RNF25[7].
References:
[1] Sharma, J., Du, M., Wong, E., Mutyam, V., Li, Y., Chen, J., Wangen, J., Thrasher, K., Fu, L., Peng, N., Tang, L., Liu, K., Mathew, B., Bostwick, R. J., Augelli-Szafran, C. E., Bihler, H., Liang, F., Mahiou, J., Saltz, J., Rab, A., … Bedwell, D. M. (2021). A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nature communications, 12(1), 4358.
[2] Hellen C. U. T. (2018). Translation Termination and Ribosome Recycling in Eukaryotes. Cold Spring Harbor perspectives in biology, 10(10), a032656.
[3] Coelho, J. P. L., Yip, M. C. J., Oltion, K., Taunton, J., & Shao, S. (2024). The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center. Nature chemical biology, 20(7), 877–884.
[4] A molecular glue degrader of eRF1 on the ribosome. (2024). Nature chemical biology, 20(7), 810–811.
[5] Oltion, K., Carelli, J. D., Yang, T., See, S. K., Wang, H. Y., Kampmann, M., & Taunton, J. (2023). An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes. Cell, 186(2), 346–362.e17.
[6] Toledano, I., Supek, F., & Lehner, B. (2024). Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules. Nature genetics, 56(9), 1914–1924.
[7] Gurzeler, L. A., Link, M., Ibig, Y., Schmidt, I., Galuba, O., Schoenbett, J., Gasser-Didierlaurant, C., Parker, C. N., Mao, X., Bitsch, F., Schirle, M., Couttet, P., Sigoillot, F., Ziegelmüller, J., Uldry, A. C., Teodorowicz, W., Schmiedeberg, N., Mühlemann, O., & Reinhardt, J. (2023). Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control. Cell reports, 42(9), 113056.
SRI-41315是一种有效的eRF1降解剂[1]。eRF1（eukaryotic release factor 1）是真核生物中的一种翻译终止因子，主要负责识别终止密码子（UAA、UAG和UGA），并催化新生肽链从核糖体的释放，从而终止蛋白质的合成[2]。SRI-41315通过在核糖体解码中心充当分子胶，诱导eRF1与核糖体紧密结合，从而增加对隐匿终止密码子的识别并触发eRF1的降解[3]。这种作用机制导致翻译终止减少，进而促进提前终止密码子（premature stop codon, PTC）的读取（readthrough），恢复因PTC导致的截短蛋白的全长表达[4]。SRI-41315通常用于研究由PTC引起的遗传性疾病，如纤维化和Hurler综合征（mucopolysaccharidosis type I, MPS I）[5-7]。
在体外实验中，用SRI-41315（5μM；24小时）处理人支气管上皮细胞，可诱导终止密码子处的长时间停顿，抑制与囊性纤维化相关的提前终止密码子（PTC），恢复囊性纤维化跨膜传导调节蛋白（CFTR）的表达和功能，降低终止因子eRF1的丰度，并增强氨基糖苷类药物介导的读通作用，从而协同增加CFTR的活性[1]。
在体内实验中，口服给予Hurler综合征大鼠SRI-41315（40mg/kg/day；14天）可通过涉及GCN1、RNF14和RNF25的核糖体相关质量控制通路触发eRF1降解，促进提前终止密码子的读取[7]。
| Cell experiment [1]: | |
Cell lines | 16HBEge G542X cells |
Preparation Method | Promoter-enhanced 16HBEge G542X cells were seeded at 2 × 105 cells per well in a 24-well plate. After 24h, the medium was replaced with medium containing 5μM SRI-41315 and cells were incubated for 24-48h. Cells were lysed in 100μL Pierce™ IP Lysis Buffer (87788) with complete protease inhibitor cocktail. Capillary electrophoresis western blot analysis was carried out with a Wes equipment and ProteinSimple reagents according to manufacturer protocols using default settings. Briefly, 4.8μL of cell lysate was mixed with 1.2μL of fluorescent master mix and heated at 95°C for 5min. The samples, blocking reagent, wash buffer, and antibodies for eRF1 (1:50), eRF3 (1:30), GAPDH (1:1000 or 1:2000), and vinculin (1:2000 or 1:5000), as well as secondary antibodies and chemiluminescent substrates, were loaded into the ProteinSimple kit microplate. The data were analyzed with Compass software. |
Reaction Conditions | 5μM; 24-48h |
Applications | SRI-41315 restores CFTR expression and function, reduces eRF1 abundance. |
| Animal experiment [2]: | |
Animal models | Hurler IDUA-W401X rat model |
Preparation Method | CRISPR engineering and genetic analysis of the Wistar Kyoto Rat-W401X animal model was performed by GenoWay. Male and female animals homozygous for the IDUA W401X mutation were used at the age of 8–10 weeks (200–300g weight) for SRI-41315 (40mg/kg/day; orally; 14 days). Treatment and control groups (vehicle, WT untreated; n = 5) were separately housed. Animal weight was measured every third day and general health was monitored daily. Pharmacokinetics was determined from tail vein and terminal blood collections. Brain tissue compound concentration was determined from collected CSF fluid. Tissues were snap frozen in liquid nitrogen and stored upon analysis. |
Dosage form | 40mg/kg/day for 14 days; p.o. |
Applications | SRI-41315 promotes readthrough of premature termination codons by triggering eRF1 degradation by a ribosome-associated quality control pathway involving GCN1, RNF14, and RNF25. |
References: | |
| Cas No. | 1613509-49-1 | SDF | Download SDF |
| 分子式 | C22H19N3O2 | 分子量 | 357.41 |
| 溶解度 | DMSO : 20.83 mg/mL (58.28 mM; Need ultrasonic) | 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 | 2.7979 mL | 13.9895 mL | 27.9791 mL |
| 5 mM | 0.5596 mL | 2.7979 mL | 5.5958 mL |
| 10 mM | 0.2798 mL | 1.399 mL | 2.7979 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: >97.00%
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