寨卡病毒（ZIKV）感染因其与基兰巴雷综合征和成人及胎儿的小头症的关联而成为全球公共卫生威胁，尤其是最近的流行病。虽然全球范围内已经进行了非凡的努力来寻找安全和有效的治疗方法，但治疗进展似乎仍然停滞不前，尤其是在治疗先天性ZIKV感染方面。从药用植物中进化优化成药物分子的生物化合物提供了准备用于制药和抗病毒药物的有资格的来源。在这里，我们在体外识别了天然存在的生物活性产物脱氧大黄酚（DES）作为六种传统多酚类化合物中对ZIKV感染具有最强抑制作用的化合物。我们还利用滋养层细胞系、人类滋养层干细胞和复杂的胎盘器官模型提供了可靠的证据来支持DES的抗ZIKV生物活性。值得注意的是，DES处理有效地减少了血清和靶组织中的ZIKV负荷，并相应地改善了ZIKV引起的病理变化，包括体重减轻、组织炎症、细胞凋亡和不良妊娠结局，而且在成年和怀孕的小鼠中并未引起明显的毒性反应。此外，机制研究揭示出DES可以通过直接靶向ZIKV E蛋白和下调ZIKV受体的可能性来抑制ZIKV进入。这些发现阐明了脱氧大黄酚对ZIKV感染的体内外保护作用，为先天性ZIKV感染的新型有效治疗的发展提供了启示。© 2023作者。由Elsevier B.V. 出版。保留所有权利。

Zika virus (ZIKV) infection arises as a global health threat owing to its association with Guillain-Barre syndrome and microcephaly in adults and fetuses since the most recent epidemics. Although extraordinary efforts have been underway globally to identify safe and effective treatments for ZIKV, therapeutic progressions seem to remain stagnant, especially for treating congenital ZIKV infection. Bio-compounds from medicinal plants evolutionarily optimized as drug-like molecules offer eligible sources of pharmaceuticals and lead drugs to fight against viral infections. Here, we identified desoxyrhapontigenin (DES), a naturally occurring bioactive product, as the strongest inhibitory compound against ZIKV infection among six conventional polyphenols in vitro. We also leveraged the trophoblast cell line, human trophoblast stem cells, and complex placental organoid models to provide solid evidence to support the anti-ZIKV bioactivity of DES. Notably, DES treatment effectively reduced the ZIKV burden in serum and target tissues, and correspondingly improved ZIKV-induced pathologic changes including weight loss, tissue inflammation, cell apoptosis, and adverse pregnancy outcomes, while it did not lead to obvious toxicity in both adult and pregnant mice. Furthermore, mechanistic studies revealed that DES could suppress ZIKV entry via dual mechanisms of direct targeting ZIKV E proteins and downregulating putative ZIKV receptors. These findings elucidate a previously unappreciated protective role of desoxyrhapontigenin against ZIKV infection both in vitro and in vivo, which shed light on the development of a novel and potent treatment for congenital ZIKV infection.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.