Drug Repurposing Screening for Zika Virus Infection

National Center For Advancing Translational Sciences

Investigators

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Abstract

Repositioning of approved drugs and clinical-stage compounds with existing preclinical and clinical data can greatly expedite the process, particularly for rare, low-prevalence diseases and for rapidly spreading infectious diseases, such as Zika virus. We developed a ZIKV NS-1 assay in the TR-FRET format for high throughput screening of compound collections. The screen identified and confirmed 134 selective inhibitors that suppressed ZIKV replication in human cells. Because the mechanisms of action and/or clinical indications of the most hits from the ZIKV NS-1 drug repurposing screen are known, we linked these confirmed compounds to the protein network identified by our collaborators at the Johns Hopkins University leading to the identification of cellular pathways critical to ZIKV replication and pathogenesis. This protein network analysis used a protein array analysis of direct interactions between 10 individual ZIKV proteins and approximately 10,000 human proteins. We also integrated the results from the RNAi screen of the druggable human genome that identified a set of host proteins involved in ZIKV replication. We found that the proteasome complex in host cells to be actively involved in ZIKV replication (Guang et al. 2021). During our assay development for compound screening, we also observed disrupted mitochondrial membrane potential and mitochondrial fragmentation after ZIKV infection in human neural stem cells and the SNB-19 glioblastoma cell line. We found that the severity of these changes correlated with the amount of ZIKV proteins in the infected cells. Further experiments found that the decreased levels of mitofusin 2 modulate mitochondria fusion after ZIKV infection. We also found that mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibiting mitochondria fission, decreased mitochondria disruptions and cell death in ZIKV-infected cells. The results suggested a relationship between the abnormal mitochondrial fragmentation and ZIKV-induced neuronal cell death (Shu Y. et al. 2020). Thus, a new therapeutic strategy for treatment of neuronal apoptosis caused by ZIKV infection could target the abnormality of mitochondrial fission-fusion in ZIKV infected cells. From our previous drug repurposing screen, Niclosamide, an anthelminthic drug, was found to inhibit ZIKV replication (Xu et al, Nature Medicine 2016). But this approved drug has poor solubility in water and low oral bioavailability. To optimize the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika, we conducted structure-activity relationship (SAR) and structure-properties relationship (SPR) studies (Shamim et al., 2021).