In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus.
In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus.
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DOI：
10.1016/j.apsb.2021.10.017
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发表时间：
2022-04
影响因子：
14.5
通讯作者：
Li, Hongmin
中科院分区：
文献类型：
--
作者：
Li, Zhong;Xu, Jimin;Lang, Yuekun;Wu, Xiangmeng;Hu, Saiyang;Samrat, Subodh Kumar;Tharappel, Anil M.;Kuo, Lili;Butler, David;Song, Yongcheng;Zhang, Qing-Yu;Zhou, Jia;Li, Hongmin
寨卡病毒（ZIKV）可导致严重的人类疾病，无需特定治疗。之前，我们发现赤藓红B（一种FDA批准的食品添加剂）抑制病毒NS 2 B − NS 3相互作用，从而抑制细胞培养物中的ZIKV感染。在该研究中，我们进行了药代动力学和体内研究以证明赤藓红B在3D微型脑类器官和小鼠模型中针对ZIKV的功效。我们的结果显示赤藓红B在消除3D类器官模型中的ZIKV复制方面非常有效。尽管药代动力学研究表明赤藓红B具有低吸收特征，但是与媒介物对照相比，通过致死剂量的ZIKV攻击的小鼠在口服施用赤藓红B后显示出显著改善的存活率。有限的结构-活性关系研究表明，在氧杂蒽环上进行修饰的赤藓红B的大多数类似物导致对病毒NS 2 B-NS 3相互作用、蛋白酶活性和抗病毒功效的抑制活性丧失或降低。相比之下，在异苯并呋喃环上引入氯取代导致活性略微增加，表明异苯并呋喃环对于修饰具有良好的耐受性。细胞毒性研究表明，所有衍生物对人体细胞无毒。总之，我们的研究证明赤藓红B在体外和体内都是针对ZIKV的有效抗病毒剂。Erythrosin B（EB）是一种FDA批准的食品染料，可以保护3D迷你脑类器官免受寨卡病毒感染。该图显示了用模拟溶液或用EB或DMSO对照处理的ZIKV PRVABC 59（绿色）感染的类器官切片的免疫荧光成像。蓝色DAPI
Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B−NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo. Erythrosin B (EB), an FDA-approved food dye, can protect 3D mini-brain organoid from infection of Zika virus. This figure shows the immunofluorescence imaging of slices of organoid infected with mock solution or ZIKV PRVABC59 (green) treated with EB or DMSO control. Blue, DAPI.
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