JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo.
JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo.
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DOI：
10.1021/acsinfecdis.0c00217
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发表时间：
2020-10-09
影响因子：
5.3
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Li Z;Xu J;Lang Y;Fan X;Kuo L;D'Brant L;Hu S;Samrat SK;Trudeau N;Tharappel AM;Rugenstein N;Koetzner CA;Zhang J;Chen H;Kramer LD;Butler D;Zhang QY;Zhou J;Li H
黄病毒会导致严重的人类疾病。最近寨卡病毒的爆发突显了开发针对这类病毒的有效疗法的必要性。以前，我们通过靶向病毒蛋白酶NS3和其辅因子NS2B之间的界面来确定氯硝柳胺是一种广谱的黄病毒抑制剂。在这里，我们筛选了一个小的氯硝柳胺衍生物文库，并确定了一种具有改善药代动力学特性的新类似物。在细胞抗病毒实验中，化合物JMX0207在抑制NS3和NS2B之间的分子相互作用方面表现出更好的效果，对病毒蛋白酶功能的抑制更好，抗病毒效果更强。该衍生物还显著降低了寨卡病毒在来源于多能神经干细胞的3D迷你脑器官上的感染。有趣的是，该化合物显著降低了寨卡病毒(ZIKV)动物模型中的病毒血症。总之，我们鉴定了一种氯硝柳胺衍生物JMX0207，它在体外和体内都显示出更好的药代动力学和抗寨卡病毒的有效性。
Flaviviruses causes significant human disease. Recent outbreaks of the Zika virus highlight the need to develop effective therapies for this class of viruses. Previously we identified niclosamide as a broad-spectrum inhibitor for flaviviruses by targeting the interface between viral protease NS3 and its cofactor NS2B. Here, we screened a small library of niclosamide derivatives and identified a new analogue with improved pharmacokinetic properties. Compound JMX0207 showed improved efficacy in inhibition of the molecular interaction between NS3 and NS2B, better inhibition of viral protease function, and enhanced antiviral efficacy in the cell-based antiviral assay. The derivative also significantly reduced Zika virus infection on 3D mini-brain organoids derived from pluripotent neural stem cells. Intriguingly, the compound significantly reduced viremia in a Zika virus (ZIKV) animal model. In summary, a niclosamide derivative, JMX0207, was identified, which shows improved pharmacokinetics and efficacy against Zika virus both in vitro and in vivo.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
64.8
作者：
Larocca, Rafael A.;Abbink, Peter;Peron, Jean Pierre S.;Zanotto, Paolo M. de A.;Iampietro, M. Justin;Badamchi-Zadeh, Alexander;Boyd, Michael;Ng'ang'a, David;Kirilova, Marinela;Nityanandam, Ramya;Mercado, Noe B.;Li, Zhenfeng;Moseley, Edward T.;Bricault, Christine A.;Borducchi, Erica N.;Giglio, Patricia B.;Jetton, David;Neubauer, George;Nkolola, Joseph P.;Maxfield, Lori F.;De La Barrera, Rafael A.;Jarman, Richard G.;Eckels, Kenneth H.;Michael, Nelson L.;Thomas, Stephen J.;Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
4.2
作者：
Chen, Haijun;Yang, Zhengduo;Ding, Chunyong;Chu, Lili;Zhang, Yusong;Terry, Kristin;Liu, Huiling;Shen, Qiang;Zhou, Jia
通讯作者：
Zhou, Jia
影响因子：
6.7
作者：
Chen, Haijun;Yang, Zhengduo;Ding, Chunyong;Chu, Lili;Zhang, Yusong;Terry, Kristin;Liu, Huiling;Shen, Qiang;Zhou, Jia
通讯作者：
Zhou, Jia
影响因子：
11.8
作者：
Foy BD;Kobylinski KC;Chilson Foy JL;Blitvich BJ;Travassos da Rosa A;Haddow AD;Lanciotti RS;Tesh RB
通讯作者：
Tesh RB