In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus  

作　　者：Zhong Li Jimin Xu Yuekun Lang Xiangmeng Wu Saiyang Hu Subodh Kumar Samrat Anil M.Tharappel Lili Kuo David Butler Yongcheng Song Qing-Yu Zhang Jia Zhou Hongmin Li 

机构地区：[1]Department of Pharmacology and Toxicology,College of Pharmacy,Tucson,AZ 85721-0207,USA [2]Wadsworth Center,New York State Department of Health,Albany,NY 12208,USA [3]Chemical Biology Program,Department of Pharmacology and Toxicology,University of Texas Medical Branch,Galveston,TX 77555,USA [4]The Neural Stem Cell Institute,Rensselaer,NY 12144,USA [5]Department of Pharmacology and Chemical Biology,Baylor College of Medicine,Houston,TX 77030,USA

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1662-1670,共9页药学学报（英文版）

基　　金：This study was partially supported by grants AI131669,AI140726,and AI141178 from the National Institute of Allergy and Infectious Diseases(NIAID,USA);the National Institutes of Health(Hongmin Li and Jia Zhou);Additionally,Jia Zhou is partly supported by the John D.Stobo,M.D.Distinguished Chair Endowment Fund at UTMB;Hongmin Li is additionally supported by NIH grants AI133219,AI134568,AI140406,and AI140491,USA;the R.Ken and Donna Coit Endowed Chair fund in Drug Discovery.

摘　　要：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.

关 键 词：FLAVIVIRUS Zika virus Dengue virus ANTIVIRAL Protease inhibitor Erythrosin B 

分 类 号：R965[医药卫生—药理学]