Effective Antiviral Activity of the Tyrosine Kinase Inhibitor Sunitinib Malate against Zika Virus

Chen-Sheng Lin; Su-Hua Huang; Bo-Yu Yan; Hsueh-Chou Lai; Cheng-Wen Lin

doi:10.3947/ic.2021.0111

Effective Antiviral Activity of the Tyrosine Kinase Inhibitor Sunitinib Malate against Zika Virus

Infect Chemother. 2021 Dec;53(4):730-740. doi: 10.3947/ic.2021.0111. Epub 2021 Nov 25.

Authors

Chen-Sheng Lin¹, Su-Hua Huang², Bo-Yu Yan³, Hsueh-Chou Lai⁴, Cheng-Wen Lin^{2

5}

Affiliations

¹ Division of Gastroenterology, Kuang Tien General Hospital, Taichung, Taiwan.
² Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
³ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
⁴ Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁵ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan. cwlin@mail.cmu.edu.tw.

Abstract

Introduction: Zika virus (ZIKV), a mosquito-borne flavivirus, causes the outbreaks of Latin America in 2015 - 2016, with the incidence of neurological complications. Sunitinib malate, an orally bioavailable malate salt of the tyrosine kinase inhibitor, is suggested as a broad-spectrum antiviral agent against emerging viruses like severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2.

Materials and methods: This study investigated the antiviral efficacy and antiviral mechanisms of sunitinib malate against ZIKV infection using cytopathic effect reduction, virus yield, and time-of-addition assays.

Results: Sunitinib malate concentration-dependently reduced ZIKV-induced cytopathic effect, the expression of viral proteins, and ZIKV yield in supernatant with 50% inhibitory concentration (IC₅₀) value of 0.015 μM, and the selectivity index of greater than 100 against ZIKV infection, respectively. Sunitinib malate had multiple antiviral actions during entry and post-entry stages of ZIKV replication. Sunitinib malate treatment at entry stage significantly reduced the levels of ZIKV RNA replication with the reduction of (+) RNA to (-) RNA ratio and the production of new intracellular infectious particles in infected cells. The treatment at post-entry stage caused a concentration-dependent increase in the levels of ZIKV (+) RNA and (-) RNA in infected cells, along with enlarging the ratio of (+) RNA to (-) RNA, but caused a pointed increase in the titer of intracellular infectious particles by 0.01 and 0.1 μM, and a substantial decrease in the titer of intracellular infectious particles by 1 μM.

Conclusion: The study discovered the antiviral actions of sunitinib malate against ZIKV infection, demonstrating a repurposed, host-targeted approach to identify potential antiviral drugs for treating emerging and global viral diseases.

Keywords: Antiviral agents; Inhibitory concentration 50; Protein kinase inhibitors; Sunitinib; Zika Virus.

Abstract

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