Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-10-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.514313/full |
| _version_ | 1818348598881943552 |
|---|---|
| author | Xiangling Cui Rui Zhou Chenchao Huang Chenchao Huang Rongyu Zhang Rongyu Zhang Jing Wang Yongxin Zhang Jiwei Ding Jiwei Ding Xiaoyu Li Jinming Zhou Jinming Zhou Jinming Zhou Shan Cen Shan Cen Shan Cen |
| author_facet | Xiangling Cui Rui Zhou Chenchao Huang Chenchao Huang Rongyu Zhang Rongyu Zhang Jing Wang Yongxin Zhang Jiwei Ding Jiwei Ding Xiaoyu Li Jinming Zhou Jinming Zhou Jinming Zhou Shan Cen Shan Cen Shan Cen |
| author_sort | Xiangling Cui |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T17:52:37Z |
| format | Article |
| id | doaj.art-cc4bd219e6674d95ad1b0f52e9a65a46 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T17:52:37Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-cc4bd219e6674d95ad1b0f52e9a65a462022-12-21T23:36:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-10-011110.3389/fphar.2020.514313514313Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease InhibitorXiangling Cui0Rui Zhou1Chenchao Huang2Chenchao Huang3Rongyu Zhang4Rongyu Zhang5Jing Wang6Yongxin Zhang7Jiwei Ding8Jiwei Ding9Xiaoyu Li10Jinming Zhou11Jinming Zhou12Jinming Zhou13Shan Cen14Shan Cen15Shan Cen16Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, ChinaDrug Discovery & Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, ChinaKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, ChinaDrug Discovery & Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaCAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, ChinaDrug Discovery & Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaCAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaMounting 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.https://www.frontiersin.org/articles/10.3389/fphar.2020.514313/fullZika virusnatural active compoundscreenanti-virusprotease |
| spellingShingle | Xiangling Cui Rui Zhou Chenchao Huang Chenchao Huang Rongyu Zhang Rongyu Zhang Jing Wang Yongxin Zhang Jiwei Ding Jiwei Ding Xiaoyu Li Jinming Zhou Jinming Zhou Jinming Zhou Shan Cen Shan Cen Shan Cen Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor Frontiers in Pharmacology Zika virus natural active compound screen anti-virus protease |
| title | Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor |
| title_full | Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor |
| title_fullStr | Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor |
| title_full_unstemmed | Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor |
| title_short | Identification of Theaflavin-3,3’-Digallate as a Novel Zika Virus Protease Inhibitor |
| title_sort | identification of theaflavin 3 3 digallate as a novel zika virus protease inhibitor |
| topic | Zika virus natural active compound screen anti-virus protease |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.514313/full |
| work_keys_str_mv | AT xianglingcui identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT ruizhou identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT chenchaohuang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT chenchaohuang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT rongyuzhang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT rongyuzhang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jingwang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT yongxinzhang identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jiweiding identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jiweiding identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT xiaoyuli identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jinmingzhou identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jinmingzhou identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT jinmingzhou identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT shancen identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT shancen identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor AT shancen identificationoftheaflavin33digallateasanovelzikavirusproteaseinhibitor |