A screen of FDA-approved drugs with minigenome identified tigecycline as an antiviral targeting nucleoprotein of Crimean-Congo hemorrhagic fever virus.
A screen of FDA-approved drugs with minigenome identified tigecycline as an antiviral targeting nucleoprotein of Crimean-Congo hemorrhagic fever virus.
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DOI：
10.1016/j.antiviral.2022.105276
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发表时间：
2022-03
影响因子：
7.6
通讯作者：
Minato Hirano;Yasuteru Sakurai;Shuzo Urata;Yohei Kurosaki;J. Yasuda;K. Yoshii
中科院分区：
文献类型：
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作者：
Minato Hirano;Yasuteru Sakurai;Shuzo Urata;Yohei Kurosaki;J. Yasuda;K. Yoshii
克里米亚-刚果出血热病毒(CCHFV)属于新城疫病毒属，是一种病原性病毒性出血性疾病，病死率为30%。然而，探索针对CCHFV的抗病毒化合物的研究有限。在这项研究中，我们开发了一个由正核病毒、CCHFV和哈扎拉病毒组成的微型基因组系统来分析病毒的复制，并筛选了FDA批准的化合物文库。小基因组组分的转染诱导荧光素酶的表达显著增加，表明报告RNA得到了充分的复制和翻译。化合物文库筛选鉴定出14个显著降低荧光素酶活性的候选化合物。其中一些化合物还抑制了传染性哈扎拉病毒的复制。进一步分析了替吉环素抑制病毒N蛋白与RNA相互作用的机制，并观察到替环素降低了病毒N蛋白与RNA的相互作用。本工作为进一步开发抗CCHFV病毒药物的动物模型验证和设计活性更强的化学衍生物奠定了基础。
Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to the genusOrthonairovirusand is the causative agent of a viral hemorrhagic disease with a case fatality rate of 30%. However, limited studies have been conducted to explore antiviral compounds specific to CCHFV. In this study, we developed a minigenome system of orthonairoviruses, CCHFV and Hazara virus to analyze viral replication and screened an FDA-approved compound library. The transfection of the minigenome components induced marked increase in luciferase expression, indicating the sufficient replication and translation of reporter RNA. Compound library screening identified 14 candidate compounds that significantly decreased luciferase activity. Some of the compounds also inhibited the replication of the infectious Hazara virus. The mechanism of inhibition by tigecycline was further analyzed, and a decrease in the interaction between the viral N protein and RNA by tigecycline was observed. This work provides a basis for validation using animal models and the design of chemical derivatives with stronger activity in future studies on the development of an antiviral against CCHFV.