Amodiaquine, an antimalarial drug, inhibits dengue virus type 2 replication and infectivity.
Amodiaquine, an antimalarial drug, inhibits dengue virus type 2 replication and infectivity.
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DOI：
10.1016/j.antiviral.2014.03.014
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发表时间：
2014-06
影响因子：
7.6
通讯作者：
Padmanabhan R
中科院分区：
文献类型：
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作者：
Boonyasuppayakorn S;Reichert ED;Manzano M;Nagarajan K;Padmanabhan R
阿莫地喹抑制登革热病毒感染的EC50和EC90分别为1.08±0.09 μM和2.69±0.47 μM。阿莫地喹抑制登革病毒报告复制子复制，EC50值为7.41±1.09 μM。阿莫地喹的对羟基苯胺和二乙胺甲基对其抗病毒活性都很重要。重新利用抗疟化合物阿莫地喹是治疗登革热病毒感染的一种有希望的选择。登革热病毒血清型1-4 （DENV1-4）由蚊子传播，在世界上引起最常见的虫媒病毒感染，每年造成约3.9亿例病例，约2.5万人死亡。目前还没有疫苗或抗病毒药物可供人类使用。含有喹啉支架的化合物对黄病毒NS2B-NS3蛋白酶（NS2B-NS3pro）具有良好的抑制作用。在这项研究中，我们筛选了喹啉衍生物，这是一种已知的抗疟疾药物，可以抑制DENV2和西尼罗病毒（WNV）的复制子表达细胞为基础的实验。4-氨基喹啉类药物阿莫地喹（Amodiaquine， AQ）抑制了DENV2的感染能力，其EC50和EC90分别为1.08±0.09 μM和2.69±0.47 μM； Renilla荧光素酶报告基因法检测了DENV2 RNA复制能力，其EC50值为7.41±1.09 μM。BHK-21细胞毒浓度（CC50）为52.09±4.25 μM。细胞外病毒粒子的斑块测定以及细胞内和细胞外病毒RNA水平的qRT-PCR证实了复制抑制作用。AQ的稳定性至少为96 h，并且对病毒生命周期的进入、翻译和复制后阶段有轻微的抑制作用。DENV蛋白酶、5 ' -甲基转移酶和RNA依赖的RNA聚合酶似乎不是AQ的靶标，对羟基苯胺和二乙基氨基甲基对AQ抑制DENV2复制和传染性都很重要。我们的结果支持AQ作为抗黄病毒治疗的一个有希望的候选者。
Amodiaquine inhibited dengue virus infectivity with EC50 and EC90 values of 1.08 ± 0.09 and 2.69 ± 0.47 μM, respectively. Amodiaquine inhibited replication of dengue virus reporter replicon with EC50 value of 7.41 ± 1.09 μM. Both p-hydroxyanilino and diethylaminomethyl moieties of amodiaquine are important for its antiviral activity. Repurposing of the antimalarial compound, amodiaquine, is a promising option for treatment of dengue virus infections. Dengue virus serotypes 1–4 (DENV1–4) are transmitted by mosquitoes which cause most frequent arboviral infections in the world resulting in ∼390 million cases with ∼25,000 deaths annually. There is no vaccine or antiviral drug currently available for human use. Compounds containing quinoline scaffold were shown to inhibit flavivirus NS2B–NS3 protease (NS2B–NS3pro) with good potencies. In this study, we screened quinoline derivatives, which are known antimalarial drugs for inhibition of DENV2 and West Nile virus (WNV) replication using the corresponding replicon expressing cell-based assays. Amodiaquine (AQ), one of the 4-aminoquinoline drugs, inhibited DENV2 infectivity measured by plaque assays, with EC50 and EC90 values of 1.08 ± 0.09 μM and 2.69 ± 0.47 μM, respectively, and DENV2 RNA replication measured by Renilla luciferase reporter assay, with EC50 value of 7.41 ± 1.09 μM in the replicon expressing cells. Cytotoxic concentration (CC50) in BHK-21 cells was 52.09 ± 4.25 μM. The replication inhibition was confirmed by plaque assay of the extracellular virions as well as by qRT-PCR of the intracellular and extracellular viral RNA levels. AQ was stable for at least 96 h and had minor inhibitory effect on entry, translation, and post-replication stages in the viral life cycle. DENV protease, 5′-methyltransferase, and RNA-dependent RNA polymerase do not seem to be targets of AQ. Both p-hydroxyanilino and diethylaminomethyl moieties are important for AQ to inhibit DENV2 replication and infectivity. Our results support AQ as a promising candidate for anti-flaviviral therapy.