2. Academic Validation
  3. Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus

Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus

  • BMC Med. 2020 Jul 31;18(1):204. doi: 10.1186/s12916-020-01663-1.
Jie Yuan 1 2 3,  Jianchen Yu 2 3 4,  Yun Huang 3,  Zhenjian He 2 5,  Jia Luo 6,  Yun Wu 2 4 7,  Yingchun Zheng 8,  Jueheng Wu 2 4 7,  Xun Zhu 2 4,  Haihe Wang 1,  Mengfeng Li 9 10 11
Affiliations

Affiliations

  • 1 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
  • 3 Cancer Institute, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 4 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 School of Public Health, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
  • 7 Southern Laboratory of Ocean Science and Engineering (Zhuhai), Zhuhai, 519000, Guangdong, China.
  • 8 School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
  • 9 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China. limf@mail.sysu.edu.cn.
  • 10 Cancer Institute, Southern Medical University, Guangzhou, 510515, Guangdong, China. limf@mail.sysu.edu.cn.
  • 11 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. limf@mail.sysu.edu.cn.
PMID: 32731873 DOI: 10.1186/s12916-020-01663-1
Abstract

Background: Zika virus (ZIKV) Infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV Infection are not available thus far.

Methods: We screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds' direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The Antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in IFNAR1-/- mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry.

Results: Here, we report that a first-in-class macrocyclic Antibiotic, which has been clinically used to treat Clostridium difficile Infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV Infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp.

Conclusions: Our data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an Antiviral therapeutic.

Keywords

Antiviral; Fidaxomicin; NS5; RdRp inhibitor; Zika virus.

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