Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Viruses. 2019 Nov 2;11(11):1019. doi: 10.3390/v11111019.
Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.
寨卡病毒（ZIKV）感染可导致严重的先天性寨卡综合征，包括小头畸形和其他神经畸形。迄今为止，尚未批准任何治疗药物用于治疗人类 ZIKV 感染；因此，需要不断努力开发有效和安全的抗病毒药物来治疗 ZIKV 引起的疾病。在筛选天然产物库后，我们在此鉴定了四种在 Vero E6 细胞中具有抗 ZIKV 活性的天然产物，包括棉酚、姜黄素、洋地黄皂甙和柯萨奇宁。除了姜黄素外，其他三种天然产物以前没有报道过具有抗 ZIKV 活性。其中，棉酚对几乎所有 10 种测试的 ZIKV 株均表现出最强的抑制活性，包括六种最近流行的人类株。机制研究表明，棉酚可以通过靶向 ZIKV 的包膜蛋白结构域 III（EDIII）来中和 ZIKV 感染。相比之下，其他天然产物通过靶向宿主细胞或与细胞相关的 ZIKV 进入和复制阶段来抑制 ZIKV 感染。棉酚与本研究中鉴定的三种天然产物中的任何一种以及以前报道的抗 ZIKV 化合物硼替佐米联合使用，对三种测试的 ZIKV 人株均表现出显著的组合抑制作用。重要的是，棉酚在体外也对所有四种血清型登革热病毒（DENV）人株表现出显著的效力。总之，这项研究表明，这些天然产物，特别是棉酚，具有进一步开发的潜力，可作为先导化合物或广谱抑制剂，用于对抗 ZIKV 和其他黄病毒，如 DENV。
