Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes.
Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes.
复制标题
DOI：
10.1093/nar/gku757
复制
发表时间：
2014
影响因子：
14.9
通讯作者：
Jemielity J
中科院分区：
文献类型：
--
作者：
Kowalska J;Wypijewska del Nogal A;Darzynkiewicz ZM;Buck J;Nicola C;Kuhn AN;Lukaszewicz M;Zuberek J;Strenkowska M;Ziemniak M;Maciejczyk M;Bojarska E;Rhoads RE;Darzynkiewicz E;Sahin U;Jemielity J
修饰的mRNA帽类似物有助于研究mRNA相关过程，并可能创造新的治疗干预措施。我们报道了11个二核苷酸帽类似物的合成和性质，这些类似物在5 ',5 ' -三磷酸链的α-， β-或γ-位置上进行了单次硼磷酸修饰。这些化合物可以潜在地作为癌细胞翻译的抑制剂或增加外源mrna在体内治疗蛋白表达的试剂。bh3类似物被测试为两种主要细胞质帽结合蛋白的底物和结合伙伴，分别是脱帽焦磷酸酶DcpS和翻译起始因子eIF4E。BH3类似物与含S的BH3类似物（S-analogs）对DcpS的敏感性不同。根据其位置的不同，硼磷酸基团削弱了与dcp的相互作用，但稳定了与eIF4E的相互作用。第一个特性使bh3类似物更稳定，第二个特性使bh3类似物作为蛋白质生物合成抑制剂更有效。m27,2′- ogppbh3pg D1和m27,2′- ogppbh3pg D2在树突状细胞中的蛋白表达分别比m27,3′- ogpppg体外转录的mRNA高2.2倍和1.7倍。肿瘤抗原的高表达会使含有m27,2 ' -OGppBH3pG D1和m27,2 ' -OGppBH3pG D2的mrna有利于抗癌免疫。
Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide cap analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5′,5′-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m27,3′-OGpppG. Higher expression of cancer antigens would make mRNAs containing m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2 favorable for anticancer immunization.
登录
查看更多内容
通过α-P-硼磷酸核苷酸抑制丙型肝炎病毒RNA依赖性RNA聚合酶：探索基于机制的HCV药物设计的潜在策略。
影响因子：
7.6
作者：
Cheek, Marcus Adrian;Sharaf, Mariam L.;Dobrikov, Mikhail I.;Shaw, Barbara Ramsay
通讯作者：
Shaw, Barbara Ramsay
影响因子：
16
作者：
Gu, MG;Fabrega, C;Lima, CD
通讯作者：
Lima, CD
影响因子：
4.8
作者：
Grudzien, E;Kalek, M;Rhoads, RE
通讯作者：
Rhoads, RE
影响因子：
4.5
作者：
Grudzien-Nogalska, Ewa;Jemielity, Jacek;Rhoads, Robert E.
通讯作者：
Rhoads, Robert E.
影响因子：
5.8
作者：
Galmarini, Carlos M.;Warren, Galya;Senanayake, Madapathage T.;Vinogradov, Serguei V.
通讯作者：
Vinogradov, Serguei V.