Bezemer Bodine, van Cleef Koen W R, Overheul Gijs J, Miesen Pascal, van Rij Ronald P
Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
Antiviral Res. 2022 Jun;202:105313. doi: 10.1016/j.antiviral.2022.105313. Epub 2022 Mar 31.
After decades of being considered non-pathogenic, Zika virus (ZIKV) emerged as an important threat to human health during the epidemic of 2015-2016. ZIKV infections are usually asymptomatic, but can cause Guillain-Barré syndrome in adults and microcephaly in newborns. As there are currently no approved antiviral drugs against ZIKV, we tested anti-ZIKV activity of compounds from the NIH Clinical Collection for which we previously showed antiviral activity against the related dengue virus. One of the top hits from the screen was lacidipine, a 1,4-dihydropyridine calcium antagonist that is approved as an antihypertensive drug. Our data show that lacidipine is antiviral against ZIKV (strain H/PF/2013) in both Vero cells and induced pluripotent stem cell (iPSC)-derived human neural progenitor cells with IC values of 3.0 μM and <50 nM, respectively. The antiviral effect was also observed against four other ZIKV strains from the African and Asian lineages. Time-of-addition and replicon assays indicated that lacidipine acts at the post-entry stage of the viral replication cycle, inhibiting viral genome replication. Lacidipine altered the subcellular distribution of free cholesterol and neutral lipids, suggesting that the antiviral effect of lacidipine is mediated by altered trafficking of lipids. Together, these results identify lacidipine as a novel inhibitor of ZIKV replication that likely disturbs trafficking of lipids needed for replication organelle formation.
在被认为无致病性数十年后，寨卡病毒（ZIKV）在2015 - 2016年的疫情期间成为对人类健康的重大威胁。ZIKV感染通常无症状，但可导致成人患格林 - 巴利综合征和新生儿患小头畸形。由于目前尚无获批的抗ZIKV抗病毒药物，我们测试了美国国立卫生研究院临床化合物库中化合物的抗ZIKV活性，我们之前已证明这些化合物对相关的登革病毒具有抗病毒活性。筛选出的最有效化合物之一是拉西地平，一种1,4 - 二氢吡啶类钙拮抗剂，已被批准用作抗高血压药物。我们的数据表明，拉西地平在Vero细胞和诱导多能干细胞（iPSC）衍生的人神经祖细胞中对ZIKV（H/PF/2013株）具有抗病毒活性，其半数抑制浓度（IC）值分别为3.0 μM和<50 nM。对来自非洲和亚洲谱系的其他四种ZIKV毒株也观察到了抗病毒作用。加样时间和复制子试验表明，拉西地平在病毒复制周期的进入后阶段起作用，抑制病毒基因组复制。拉西地平改变了游离胆固醇和中性脂质的亚细胞分布，表明拉西地平的抗病毒作用是由脂质转运改变介导的。总之，这些结果确定拉西地平是一种新型的ZIKV复制抑制剂，可能会干扰复制细胞器形成所需脂质的转运。
