1. Academic Validation
  2. Identification of Theaflavin-3,3'-Digallate as a Novel Zika Virus Protease Inhibitor

Identification of Theaflavin-3,3'-Digallate as a Novel Zika Virus Protease Inhibitor

  • Front Pharmacol. 2020 Oct 21;11:514313. doi: 10.3389/fphar.2020.514313.
Xiangling Cui 1 Rui Zhou 1 Chenchao Huang 2 3 Rongyu Zhang 2 3 Jing Wang 1 Yongxin Zhang 1 Jiwei Ding 1 4 Xiaoyu Li 1 Jinming Zhou 1 2 3 Shan Cen 1 4 5
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • 2 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China.
  • 3 Drug Discovery & Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China.
  • 4 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
  • 5 Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Abstract

Mounting evidence indicates that Zika virus (ZIKV) is closely related to neurological disorders such as microcephaly and Guillain-Barré syndrome. There are currently no effective vaccines and FDA-approved inhibitors against ZIKV Infection. The flaviviral heterodimeric serine protease NS2B-NS3 plays an essential role in ZIKV maturation and replication, thus becoming a promising target in anti-ZIKV therapy. Herein, we developed a fluorescence-based screening assay to search for inhibitors targeting the ZIKV NS2B-NS3 protease (ZIKVpro), and identified theaflavin-3,3'-digallate (ZP10), a natural active compound derived from black tea, as a potent ZIKV protease inhibitor in vitro (IC50 = 2.3 μM). ZP10 exhibited dose-dependent inhibitory effect on ZIKV replication (EC50 = 7.65 μM). Western blot analysis suggested that ZP10 inhibited the cleavage processing of viral polyprotein precursor in cells either infected with ZIKV or expressing minimal self-cleaving proteinase NS2B-3 protease, resulting in inhibition of virus growth. Moreover, ZP10 was showed to directly bind to ZIKVpro, and a docking model further revealed that ZP10 interacted with several critical residues at the proteolytic cavity of the ZIKVpro. This study highlights that ZP10 has anti-ZIKV potency through ZIKVpro inhibition, which indicates its potential application in anti-ZIKV therapy.

Keywords

Zika virus; anti-virus; natural active compound; protease; screen.

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