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. 2023 Apr 27;15(5):1068.
doi: 10.3390/v15051068.

Repurposing of Doramectin as a New Anti-Zika Virus Agent

Yujia Zhu  1   2 , Minqi Liang  1   2 , Jianchen Yu  3   4 , Bingzhi Zhang  5 , Ge Zhu  4 , Yun Huang  6 , Zhenjian He  1   2 , Jie Yuan  2   4
Affiliations

Repurposing of Doramectin as a New Anti-Zika Virus Agent

Yujia Zhu et al. Viruses. .

Abstract

Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for ZIKV are still essential. In this study, we identified doramectin, an approved veterinary antiparasitic drug, as a novel anti-ZIKV agent (EC50 value from 0.85 μM to 3.00 μM) with low cytotoxicity (CC50 > 50 μM) in multiple cellular models. The expression of ZIKV proteins also decreased significantly under the treatment of doramectin. Further study showed that doramectin directly interacted with the key enzyme for ZIKV genome replication, RNA-dependent RNA polymerase (RdRp), with a stronger affinity (Kd = 16.9 μM), which may be related to the effect on ZIKV replication. These results suggested that doramectin might serve as a promising drug candidate for anti-ZIKV.

Keywords: RdRp; ZIKV; antiviral agent; doramectin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structure of doramectin.
Figure 2
Figure 2
Antiviral activity and cytotoxicity spectrum of doramectin in Vero, A549, and SNB19 cells. ZIKV titer was quantified by plaque reduction assay and cell viability was detected by MTT assay.
Figure 3
Figure 3
Doramectin inhibits the expression of ZIKV proteins. Western blotting analysis of protein expression of ZIKV NS5 and E in the cell lysates of Vero, A549, and SNB19 for the anti-ZIKV activity of doramectin or DMSO at indicated concentrations at 48 h post-infection (hpi) (MOI = 0.2).
Figure 4
Figure 4
Doramectin prevents cells from ZIKV infection. (A) Immunofluorescence staining for ZIKV-E in ZIKV-infected A549 cells (MOI = 2) under the treatment by DMSO or 2.5 μM doramectin. Cell nuclei were stained with DAPI (blue). ZIKV-E protein was indicated in green (Scale bar, 100 μm). (B) Quantification of the number of ZIKV+ cells relative to mock infection is shown in the histogram. * p < 0.05.
Figure 5
Figure 5
Doramectin directly binds to ZIKV RdRp. (A) Structural model for doramectin binding to the ZIKV NS5 protein was performed with Molecular Operating Environment (MOE). The NS5 protein is displayed as ribbons with the RdRp domain in red, MTase domain in yellow, and doramectin shown as green sticks. (B) Two-dimensional ligand-interaction maps of co-crystals of ZIKV NS5 domains bound with doramectin were generated using MOE. Polar residues are colored light purple, charged residues have an additional blue ring, and lipophilic residues are green. The degree of solvent exposure is shown by the blue halos. H-bond interactions to the amino acid side chain or main chain are shown as dashed green arrows, pointing toward the H-bond acceptor. (C) Coomassie blue-stained SDS-PAGE (lane 1) of crude extracts and western blot probed with anti-ZIKV NS5 (lane 2) after purification. (D,E) The surface plasmon resonance biosensor (SPR) assay to examine and characterize the binding of doramectin (D) or ribavirinc (E) to ZIKV RdRp. The Kd values were calculated via the BIAcore T100 analysis software (BIAevaluation Version 3.1).
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Grants and funding

This research was funded by Guangdong Marine Economy Development Special Project, No. GDNRC [2022]35 and GDNRC[2023]39, Natural Science Foundation of Guangdong Province, China, Grant No. 2022A1515011037, and National Natural Science Foundation of China (no. 81971146 and 82171675).