Virus Research Group, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Republic of Korea.
Sci Rep. 2019 Jun 18;9(1):8682. doi: 10.1038/s41598-019-45095-1.
Dengue fever is one of the most important mosquito-borne viral infections in large parts of tropical and subtropical countries and is a significant public health concern and socioeconomic burden. There is an urgent need to develop antivirals that can effectively reduce dengue virus (DENV) replication and decrease viral load. Niclosamide, an antiparasitic drug approved for human use, has been recently identified as an effective antiviral agent against a number of pH-dependent viruses, including flaviviruses. Here, we reveal that neutralization of low-pH intracellular compartments by niclosamide affects multiple steps of the DENV infectious cycle. Specifically, niclosamide-induced endosomal neutralization not only prevents viral RNA replication but also affects the maturation of DENV particles, rendering them non-infectious. We found that niclosamide-induced endosomal neutralization prevented E glycoprotein conformational changes on the virion surface of flaviviruses, resulting in the release of non-infectious immature virus particles with uncleaved pr peptide from host cells. Collectively, our findings support the potential application of niclosamide as an antiviral agent against flavivirus infection and highlight a previously uncharacterized mechanism of action of the drug.
登革热是热带和亚热带国家大部分地区最重要的蚊媒病毒感染之一，是一个重大的公共卫生和社会经济负担。因此，迫切需要开发能够有效抑制登革病毒（DENV）复制和降低病毒载量的抗病毒药物。氯硝柳胺是一种已被批准用于人类的驱虫药物，最近被鉴定为一种针对多种 pH 依赖性病毒（包括黄病毒）的有效抗病毒药物。在这里，我们揭示了氯硝柳胺对低 pH 细胞内区室的中和作用会影响 DENV 感染周期的多个步骤。具体来说，氯硝柳胺诱导的内体中和不仅可以防止病毒 RNA 的复制，还会影响 DENV 颗粒的成熟，使其失去感染性。我们发现，氯硝柳胺诱导的内体中和会阻止黄病毒衣壳表面 E 糖蛋白的构象变化，导致未切割的 pr 肽从宿主细胞中释放出无感染性的不成熟病毒颗粒。总之，我们的研究结果支持氯硝柳胺作为一种抗黄病毒感染的抗病毒药物的应用，并强调了该药物的一种以前未被描述的作用机制。
