Synthesis of Adenine Dinucleosides 2′,5′-Bridged by Sulfur-Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′-O-Methyltransferases
Synthesis of Adenine Dinucleosides 2′,5′-Bridged by Sulfur-Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′-O-Methyltransferases
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DOI：
10.1002/ejoc.201901120
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发表时间：
2019-09-12
影响因子：
2.8
通讯作者：
Debart, Francoise
中科院分区：
文献类型：
--
作者：
Ahmed-Belkacem, Rostom;Ortiz, Priscila Sutto;Debart, Francoise
在病毒感染过程中，病毒核糖核酸2‘-O-甲基转移酶通过催化核苷N1 2’-羟基5‘端核糖帽结构的甲基化，或以S-腺苷-L-蛋氨酸为甲基供体，诱导核糖核酸序列中腺苷的内部2’-O-甲基化，从而在病毒感染过程中诱导宿主细胞的天然抗病毒反应。我们的目标是合成模拟RNA 2‘-O-甲基化过渡态的双底物SAM类似物，以阻断病毒2’-O-甲基转移酶并对抗新出现的病毒。在这里，我们设计并合成了五个二核苷，方法是将代表SAM的5‘-硫代腺苷与另一个模拟RNA底物的腺苷单元的2’-OH连接起来，通过不同大小的含硫连接物，如烷基硫醚连接物、亚砜或砜衍生物，或二硫键。
Viral RNA 2 '-O-methyltransferases play a crucial role for luring the host cell innate antiviral response during a viral infection by catalyzing either the methylation of the 5 '-end RNA cap-structure at 2 '-OH of nucleoside N1 or by inducing internal 2 '-O-methylation of adenosines within RNA sequence using S-adenosyl-l-methionine (SAM) as the methyl donor. Our goal is to synthesize bisubstrate SAM analogues mimicking the transition state of the 2 '-O-methylation of the RNA in order to block viral 2 '-O-methyltransferases and struggle against emerging viruses. Here we designed and synthesized five dinucleosides by connecting a 5 '-thioadenosine representing the SAM to the 2 '-OH of another adenosine unit mimicking the RNA substrate, via various sized sulfur-containing linkers such as alkylthioether linkers, sulfoxide or sulfone derivatives, or a disulfide bond.