Identification of novel anti-ZIKV drugs from viral-infection temporal gene expression profiles

ABSTRACT

Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain–Barré syndrome in adults, and microcephaly in newborns). There are currently no specific therapy or vaccine options available to prevent ZIKV infections. Temporal gene expression profiles of ZIKV-infected human brain microvascular endothelial cells (HBMECs) were used in this study to identify genes essential for viral replication. These genes were then used to identify novel anti-ZIKV agents and validated in publicly available data and functional wet-lab experiments. Here, we found that ZIKV effectively evaded activation of immune response-related genes and completely reprogrammed cellular transcriptional architectures. Knockdown of genes, which gradually upregulated during viral infection but showed distinct expression patterns between ZIKV- and mock infection, discovered novel proviral and antiviral factors. One-third of the 74 drugs found through signature-based drug repositioning and cross-reference with the Drug Gene Interaction Database (DGIdb) were known anti-ZIKV agents. In cellular assays, two promising antiviral candidates (Luminespib/NVP-AUY922, L-161982) were found to reduce viral replication without causing cell toxicity. Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future.

KEYWORDS:

• ZIKV
• temporal transcriptome
• drug repurposing
• antivirals
• viral infection mechanisms

Acknowledgments

We thank Prof. Cui Min (State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China) for providing us with Human brain endothelial cells (HBMECs, passage 6, 10). N.Z. and Z.Z, conceived the project and designed the study. N.Z. wrote the paper. N.Z. designed and performed bioinformatics, drug repurposing, cheminformatics analysis and interpreted results. Z.T., N.Z., J.W., SZ., Y.L., J.M., C.J., designed and performed cell and viral experiments. N.Z. Z.Z., B.L. Z.T. and H.W. contributed to discussion and reviewed and edited the manuscript. All authors reviewed, edited the manuscript and approved the final manuscript. N.Z. and Z.Z. supervised the project.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Key Research and Development Project 2018YFA0507201, the fellowship of China Postdoctoral Science Foundation (2021M703452), Knowledge Innovation Program of Wuhan-Shuguang Project (2022020801020155).