期刊
ANTIVIRAL RESEARCH
卷 145, 期 -, 页码 33-43出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2017.07.007
关键词
Zika; Flavivirus; Novobiocin; Protease; Treatment; Molecular modelling
资金
- Centro de Alto Rendimiento de la Region de Murcia [CFE-CAR-23/15]
- Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases of the Department of Health, Hong Kong Special Administrative Region
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
- Ministry of Education of China
- Fundacion Seneca del Centro de Coordinacion de la Investigation de la Region de Murcia [18946/JLI/13, 19419/PI/14-1]
Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. (C) 2017 Elsevier B.V. All rights reserved.
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