Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.
Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.
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DOI：
10.1021/acsomega.3c02815
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发表时间：
2023-08-01
期刊：
影响因子：
4.1
通讯作者：
Nencka, Radim
中科院分区：
文献类型：
--
作者：
Stefek, Milan;Chalupska, Dominika;Chalupsky, Karel;Zgarbova, Michala;Dvorakova, Alexandra;Krafcikova, Petra;Li, Alice Shi Ming;Sala, Michal;Dejmek, Milan;Otava, Tomas;Chaloupecka, Ema;Kozak, Jaroslav;Kozic, Jan;Vedadi, Masoud;Weber, Jan;Mertlikova-Kaiserova, Helena;Nencka, Radim
寻找针对Covid-19及其因果剂SARS-COV-2的新药是当前药物化学的主要趋势之一。靶向上限机械可能是基于独特的作用机理的治疗概念之一。病毒RNA帽合成涉及两个甲基化步骤，其中第一个是由NSP14蛋白介导的。在这里，我们合理设计和合成了一系列能够与S-腺苷-L-甲硫氨酸和SARS-COV-2 NSP14 NSP14 N7-甲基转移酶的RNA结合位点结合的化合物。这些杂化分子表现出极好的效力，对各种人类甲基转移酶的高选择性，无毒性和高细胞渗透性。尽管针对酶的活性出色，但我们的化合物在体外表现出抗病毒性能不佳。这表明该病毒甲基转移酶的活性对细胞水平的病毒转录和复制没有显着影响。因此，我们的化合物代表了进一步探索SARS-COV-2 NSP14甲基转移酶在病毒生命周期和COVID-19的发病机理中的作用的独特工具。
The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 N7-methyltransferase. These hybrid molecules showed excellent potency, high selectivity toward various human methyltransferases, nontoxicity, and high cell permeability. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase has no significant effect on virus transcription and replication at the cellular level. Therefore, our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in the viral life cycle and the pathogenesis of COVID-19.
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影响因子：
4.2
作者：
Jung, Eunkyung;Soto-Acosta, Ruben;Xie, Jiashu;Wilson, Daniel J.;Dreis, Christine D.;Majima, Ryuichi;Edwards, Tiffany C.;Geraghty, Robert J.;Chen, Liqiang
通讯作者：
Chen, Liqiang
影响因子：
6.7
作者：
Ahmed-Belkacem, Rostom;Sutto-Ortiz, Priscila;Debart, Francoise
通讯作者：
Debart, Francoise
影响因子：
5.4
作者：
Case, James Brett;Ashbrook, Alison W.;Denison, Mark R.
通讯作者：
Denison, Mark R.
影响因子：
5.6
作者：
Jones, G;Willett, P;Taylor, R
通讯作者：
Taylor, R
影响因子：
3.6
作者：
Kielkowski, Pavel;Pohl, Radek;Hocek, Michal
通讯作者：
Hocek, Michal