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

• Main Authors: Xiangling Cui (Author), Rui Zhou (Author), Chenchao Huang (Author), Rongyu Zhang (Author), Jing Wang (Author), Yongxin Zhang (Author), Jiwei Ding (Author), Xiaoyu Li (Author), Jinming Zhou (Author), Shan Cen (Author)
• Format: Book
• Published: Frontiers Media S.A., 2020-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2020.514313
• Keywords: Zika virus; natural active compound; screen; anti-virus; protease; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 11 (2020)

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.