Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-18 DOI:10.1016/j.bioorg.2024.107894

Qishu Chen, Qifan Zhou, Sidi Yang, Fan Pan, Hongqi Tao, Yuanmei Wen, Yang Chao, Cailing Xie, Weixin Ou, Deyin Guo, Yingjun Li, Xumu Zhang

{"title":"Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection.","authors":"Qishu Chen, Qifan Zhou, Sidi Yang, Fan Pan, Hongqi Tao, Yuanmei Wen, Yang Chao, Cailing Xie, Weixin Ou, Deyin Guo, Yingjun Li, Xumu Zhang","doi":"10.1016/j.bioorg.2024.107894","DOIUrl":null,"url":null,"abstract":"Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC50 of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107894"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2024.107894","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC₅₀ of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.

查看原文本刊更多论文

鉴定作为 nsp14 N7-甲基转移酶抑制剂的腺苷类似物，以治疗冠状病毒感染。

冠状病毒是随着时间推移与人类和动物共同进化的 RNA 病毒，在流行病爆发时表现出很高的变异率和死亡率。非结构蛋白（nsp14）对冠状病毒的各种过程至关重要，包括基因组复制、蛋白质翻译、病毒粒子组装以及通过 RNA 甲基化修饰逃避宿主免疫。本研究设计、合成并评估了一系列腺苷类似物的抑制活性。其中，MTI013 对 nsp14 MTase 的抑制和抗病毒活性最强，在感染 HCoV-229E 的 Huh7 细胞中的 IC50 为 10.33 μM，且细胞毒性较低。当与 RdRp 抑制剂 ATV014 联用时，MTI013 显示出协同抗病毒效果，这表明它具有独立治疗和联合治疗的潜力。此外，MTI013 对 SARS-CoV-2 nsp10-nsp16 复合物和五种人类甲基转移酶具有高度选择性。这些结果为今后探索将 nsp14 作为 SARS-CoV-2 和其他冠状病毒的药物靶点提供了宝贵的结构见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.