Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USA.
Laboratory of Biochemical Pharmacology Emory University, Emory University, Atlanta, GA 30322, USA.
EBioMedicine. 2019 Sep;47:269-283. doi: 10.1016/j.ebiom.2019.08.060. Epub 2019 Sep 6.
Flaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection of medical personnel in ZIKV-affected areas.
Here, we showed that the small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both in vitro and in vivo. DGP potently blocked ZIKV infection across all human and monkey cell lines tested. DGP also displayed broad-spectrum antiviral activity against other flaviviruses. Remarkably, DGP prevented ZIKV-induced mortality in mice lacking the type I interferon receptor (Ifnar1). Cellular and virological experiments showed that DGP blocked ZIKV at a pre-fusion step or during fusion, which prevented the delivery of viral contents into the cytosol of the target cell. Mechanistic studies revealed that DGP prevented the acidification of endosomal/lysosomal compartments in target cells, thus inhibiting ZIKV fusion with cellular membranes and infection.
These investigations revealed that DGP inhibits ZIKV infection in vitro and in vivo.
The small molecule DGP has great potential for preclinical studies and the ability to inhibit ZIKV infection in humans.
黄病毒（如 Zika 病毒）会在全球范围内引起零星的大流行疫情。目前急需抗 Zika 病毒（ZIKV）药物，以预防母婴垂直传播 ZIKV、高危人群的新发感染，以及 ZIKV 疫区医务人员的感染。
在这里，我们表明小分子 6-脱氧葡萄糖二苯乙烯（DGP）在体外和体内均具有抗 ZIKV 活性。DGP 可有效抑制所有测试的人源和猴源细胞系中的 ZIKV 感染。DGP 还对其他黄病毒表现出广谱抗病毒活性。值得注意的是，DGP 可预防缺乏 I 型干扰素受体（Ifnar1）的小鼠感染 Zika 病毒引起的死亡。细胞和病毒学实验表明，DGP 在融合前或融合阶段阻断 ZIKV，从而阻止病毒内容物进入靶细胞的细胞质。机制研究表明，DGP 可防止靶细胞内体/溶酶体区室酸化，从而抑制 Zika 病毒与细胞膜融合和感染。
这些研究表明，DGP 可抑制 ZIKV 在体外和体内的感染。
小分子 DGP 具有很大的临床前研究潜力，能够抑制人类感染 Zika 病毒。
