Antiviral activity of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones against chikungunya virus targeting the viral capping nsP1
Antiviral activity of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones against chikungunya virus targeting the viral capping nsP1
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DOI：
10.1016/j.antiviral.2017.06.003
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发表时间：
2017-08-01
影响因子：
7.6
通讯作者：
Perez-Perez, Maria-Jesus
中科院分区：
文献类型：
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作者：
Gigante, Alba;Gomez-SanJuan, Asier;Perez-Perez, Maria-Jesus
基孔肯雅病毒(CHIKV)是一种通过伊蚊传播给人类的重新出现的甲型病毒。自2005年以来，CHIKV一直在全球范围内传播，导致非洲、印度洋岛屿、亚洲以及最近在美洲发生的流行病。因此，CHIKV被认为是一个全球卫生问题。目前还没有专门的疫苗或药物来治疗这种使人丧失能力的病毒感染。我们以前发现3-aryl-[1，2，3]triazolo[4，5-d]pyrimidin-7(6H)-ones是CHIKV复制的选择性抑制物，并提出了病毒封闭酶NsP1作为靶点。这项工作描述了一系列新的相关化合物的合成，这些化合物在芳基部分带有甲基酮和相关的肟类化合物，并在三唑并嘧啶酮的5-位与乙基或乙基模拟物结合。根据病毒产量降低和病毒诱导的细胞杀伤抑制试验，这些化合物在很低的MUM范围内对不同的CHIKV分离株显示出抗病毒活性。此外，这些抗病毒药物在体外抑制甲型病毒NSPL的鸟酰化作用，这是通过使用抗CAP抗体的Western印迹确定的。因此，所获得的数据似乎表明，抗CHIKV活性可能与抑制病毒RNA封顶机制中的这一关键步骤有关。(C)2017年作者。爱思唯尔出版公司(Elsevier B.V.)
Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by Aedes mosquitoes. Since 2005, CHIKV has been spreading worldwide resulting in epidemics in Africa, the Indian Ocean islands, Asia and more recently in the Americas. CHIKV is thus considered as a global health concern. There is no specific vaccine or drug available for the treatment of this incapacitating viral infection. We previously identified 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as selective inhibitors of CHIKV replication and proposed the viral capping enzyme nsP1 as a target. This work describes the synthesis of novel series of related compounds carrying at the aryl moiety a methylketone and related oximes combined with an ethyl or an ethyl-mimic at 5-position of the triazolopyrimidinone. These compounds have shown antiviral activity against different CHIKV isolates in the very low mu M range based on both virus yield reduction and virus-induced cell-killing inhibition assays. Moreover, these antivirals inhibit the in vitro guanylylation of alphavirus nsPl, as determined by Western blot using an anti-cap antibody. Thus, the data obtained seem to indicate that the anti-CHIKV activity might be related to the inhibition of this crucial step in the viral RNA capping machinery. (C) 2017 The Authors. Published by Elsevier B.V.