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]。