Drug Repurposing Screening for Zika Virus Infection

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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 have developed ZIKV NS-1 assay in the TR_FRET assay format for high throughput screening of compound collections. This assay can be used to measure ZIKV replication in host cells as the NS-1 protein is expressed during ZIKV replication. Through a drug repurposing screen using this ZIKV NI-1 assay, we have identified and confirmed 134 selective inhibitors that suppressed ZIKV replication in human cells. Among these 134 inhibitors of ZIKV replication, 33 are FDA approved drugs, 4 are approved in Canada and Japan, and 5 are investigational drugs. The rest are bioactive compounds with known mechanisms of action. These compounds can be further studied in the in vivo ZIKV models and have potential to be further developed in clinical trials for treatment of ZIKV infection. In addition, we developed a high-throughput ZIKV titer assay that can be used for rapid screening of compounds identified in other screening assays. We have also studied the protein-protein interaction networks of ZIKV with host cells. This has identified cellular pathways critical to ZIKV replication and pathogenesis. We used a protein array analysis of direct interactions between 10 individual ZIKV proteins and approximately 10,000 human proteins, which identified several cellular pathways and protein complexes. An RNAi screen of the druggable human genome identified a set of host proteins involved in ZIKV replication. The proteasome complex in host cells has been found to be actively involved in ZIKV replication. This study yielded a large set of data including protein-protein interaction, drug repurposing screening, and RNAi screening that have potential utility for other researchers to study ZIKV pathogenesis and reveal new targets for drug development. From our previous drug repurposing screen, niclosamide, an anthelminthic drug, was found to inhibit ZIKV replication (Xu et al, Nature Medicine 2016). However, this approved drug has poor solubility in water and low oral bioavailability. Our medicinal chemists have used a prodrug approach to improve the bioavailability issue of niclosamide. The chemistry effort led to TRND00507788, a Niclosamide prodrug that has excellent water solubility (>43 ug/mL at pH 7.4 buffer) and good oral bioavailability in mice. Additional studies of pharmacokinetics and in vivo activity are ongoing. Recently, this niclosamide prodrug was tested in a cytopathic effect assay of SARS-CoV-2, demonstrating an ability to suppress the cytopathic effect of viral infection in human cells.