Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus.
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.
['Yuan|Jie|J|', 'Yu|Jianchen|J|', 'Huang|Yun|Y|', 'He|Zhenjian|Z|', 'Luo|Jia|J|', 'Wu|Yun|Y|', 'Zheng|Yingchun|Y|', 'Wu|Jueheng|J|', 'Zhu|Xun|X|', 'Wang|Haihe|H|', 'Li|Mengfeng|M|']
D000818:Animals D045744:Cell Line, Tumor D002522:Chlorocebus aethiops D005260:Female D000077732:Fidaxomicin D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D008297:Male D051379:Mice D012324:RNA-Dependent RNA Polymerase D014709:Vero Cells D000071243:Zika Virus Infection
Fidaxomicin RdRp inhibitor Zika virus Antiviral NS5