Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase
Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase
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DOI：
10.1016/j.ejmech.2020.112557
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发表时间：
2020-09-01
影响因子：
6.7
通讯作者：
Debart, Francoise
中科院分区：
文献类型：
--
作者：
Ahmed-Belkacem, Rostom;Sutto-Ortiz, Priscila;Debart, Francoise
已知新病毒的传播会引发全球人类健康威胁。由近期出现的新冠病毒SARS-CoV - 2引发的当前新冠肺炎大流行，是在缺乏适当治疗的情况下，世界未来面对新出现病毒时必须面对的一个重大且不幸的例子。发现有效且特异的抗病毒抑制剂和/或疫苗来对抗这些大规模疫情爆发是一项紧迫的研究重点。参与病毒加帽途径的酶，更具体地说是RNA N7 - 或2'O - 甲基转移酶（MTases），现在被认为是抗病毒化学疗法的潜在靶点。我们通过模拟帽RNA的2'-O - 甲基化过渡态设计了双底物抑制剂，以阻断病毒的2'-O - MTases。这项工作合成了16种腺嘌呤二核苷，两个腺苷由各种含氮连接体连接。出乎意料的是，所有双底物化合物对几种黄病毒或SARS - CoV的2'-O - MTases几乎没有活性，但令人惊讶的是，其中7种在微摩尔到亚微摩尔范围内对SARS - CoV N7 - MTase（nsp14）显示出高效且特异的抑制作用。所鉴定出的最具活性的nsp14抑制剂与广谱MTase抑制剂辛伐他汀一样有效，但特异性更强。分子对接表明，该抑制剂与由S - 腺苷甲硫氨酸（SAM）和帽RNA结合位点形成的口袋结合，这在SARS - CoV nsp14中是保守的。这些二核苷SAM类似物将作为开发针对SARS - CoV - 2 nsp14 N7 - MTase的下一代抑制剂的起点。（C）2020爱思唯尔马松公司。保留所有权利。
The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2'O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2'-O-methylation of the cap RNA in order to block viral 2'-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2'-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase. (C) 2020 Elsevier Masson SAS. All rights reserved.