Discovery of Zika Virus NS2B/NS3 Inhibitors That Prevent Mice from Life-Threatening Infection and Brain Damage

被引：23

作者：

Coluccia, Antonio ^{[1
]}

Puxeddu, Michela ^{[1
]}

Nalli, Marianna ^{[1
]}

Wei, Chih-Ku ^{[2
]}

Wu, Yu-Hsuan ^{[3
]}

Mastrangelo, Eloise ^{[4
,5
]}

Elamin, Tasneem ^{[5
]}

Tarantino, Delia ^{[4
,5
]}

Bugert, Joachim Jakob ^{[6
]}

Schreiner, Benno ^{[6
]}

Nolte, Juliane ^{[6
]}

Schwarze, Frank ^{[6
]}

La Regina, Giuseppe ^{[1
]}

Lee, Jin-Ching ^{[7
,8
]}

Silvestri, Romano ^{[1
]}

机构：

[1] Sapienza Univ Rome, Dept Drug Chem & Technol, Cenci Bolognetti Fdn, Lab Affiliated Inst Pasteur Italy, I-00185 Rome, Italy

[2] Kaohsiung Med Univ, Coll Life Sci, Dept Biotechnol, Kaohsiung, Taiwan

[3] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan, Taiwan

[4] CNR, Biophys Inst, I-20133 Milan, Italy

[5] Univ Milan, Dept Biosci, I-20133 Milan, Italy

[6] Bundeswehr Inst Microbiol, Munich, Germany

[7] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Grad Inst Med,Dept Med Res, Coll Med,Dept Biotechnol,Coll Life Sci,PhD Progra, Kaohsiung, Taiwan

[8] Kaohsiung Med Univ, Drug Dev & Value Creat Res Ctr, Kaohsiung, Taiwan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 10期

关键词：

Zika; NS2B/NS3; protease; mouse model; modeling; synthesis; NS2B-NS3; PROTEASE; DISEASE; DENGUE;

D O I：

10.1021/acsmedchemlett.9b00405

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Zika virus (ZIKV) infection, which initially was endemic only in Africa and Asia, is rapidly spreading throughout Europe, Oceania, and the Americas. Although there have been enormous efforts, there is still no approved drug to treat ZIKV infection. Herein, we report the synthesis and biological evaluation of agents with noncompetitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allosteric site. Compounds 1 and 2 showed potent activity in both enzymatic and cellular assays. Derivative 1 efficiently reduced the ZIKV protein synthesis and the RNA replication and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.

引用

页码：1869 / 1874

页数：6

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