INHIBITION OF EUKARYOTIC TRANSLATION BY ANALOGS OF MESSENGER-RNA 5'-CAP - CHEMICAL AND BIOLOGICAL CONSEQUENCES OF 5'-PHOSPHATE MODIFICATIONS OF 7-METHYLGUANOSINE 5'-MONOPHOSPHATE
INHIBITION OF EUKARYOTIC TRANSLATION BY ANALOGS OF MESSENGER-RNA 5'-CAP - CHEMICAL AND BIOLOGICAL CONSEQUENCES OF 5'-PHOSPHATE MODIFICATIONS OF 7-METHYLGUANOSINE 5'-MONOPHOSPHATE
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DOI：
10.1021/bi00388a028
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发表时间：
1987-07-14
期刊：
影响因子：
2.9
通讯作者：
TAHARA, SM
中科院分区：
文献类型：
--
作者：
DARZYNKIEWICZ, E;EKIEL, I;TAHARA, SM
通过用sbd. H、sbd. CH 3或sbd. NH 2替换sbd.O，合成了具有修饰的5“-磷酸部分的7-甲基鸟苷5”-单磷酸（m7 GMP）的新类似物。用8-甲基-或8-氨基鸟嘌呤碱基取代或开环核糖（2“，3”-二醇）合成另外的类似物。用~ 1H和~（31）P NMR分析了这些化合物的溶液构象。此外，还分析了它们作为mRNA 5“-帽类似物的生物活性，通过竞争作为网织红细胞裂解物中的翻译抑制剂。用. sbd.H和. sbd. CH 3取代4“-单磷酸部分上的氧会降低帽类似物作为竞争性抑制剂的活性;然而，用. sbd.NH2取代并不会降低类似物作为抑制剂的活性。从该结果推断，帽结合蛋白需要氢键受体，而不是仅需要α-氨基上的第二阴离子基团。磷酸部分。用C8-取代的m7 GMP类似物获得的抑制结果表明，8-氨基衍生物是比8-甲基衍生物m7 GMP更好的抑制剂。前者主要是反的，而后者主要是顺的糖苷键构象。这一结果进一步支持了反构象是帽结构与帽结合蛋白相互作用的优选形式的模型。m7 GMP的2“，3”-二醇衍生物作为翻译抑制剂是无活性的。
New analogues of 7-methylguanosine 5''-monophosphate (m7GMP) were synthesized with modified 5''-phosphate moieties by replacement of .sbd.O with .sbd.H, .sbd.CH3, or .sbd.NH2. Additional analogues were synthesized with 8-methyl- or 8-aminoguanine base substitutions or ring-opened ribose (2'',3''-diol). These compounds were analyzed by 1H and 31P NMR for solution conformation. In addition, they were also analyzed for biological activity as analogues of mRNA 5''-caps by competition as inhibitors of translation in reticulocyte lysate. Substitution of oxygen on the 4''-monophosphate moiety by .sbd.H and .sbd.CH3 diminished the activity of the cap analogue as a competitive inhibitor; however, replacement by .sbd.NH2 did not diminish the activity of the analogue as an inhibitor. It was inferred from this result that cap binding proteins require a hydrogen bond acceptor as opposed to having an exclusive requirement for a second anionic group on the .alpha.-phosphate moiety. Inhibition results obtained with C8-substituted m7GMP analogues indicated that the 8-amino derivative was a better inhibitor than the 8-methyl derivative m7GMP. The former is primarily anti whereas the latter is primarily syn with respect to glycosidic bond conformation. This result further supports the model that the anti conformation is the preferred form of the cap structure for interaction with cap binding proteins. The 2'',3''-diol derivative of m7GMP was inactive as an inhibitor of translation.