UCLA researchers from the Molecular and Medical Pharmacology Department and CNSI have identified antiviral compounds that effectively inhibit Zika virus infection and cytopathic effects, potentially leading to improved therapeutics and treatment outcomes.
BACKGROUND: Zika virus (ZIKV), a flavivirus now endemic to several regions globally, can cause neurological complications, adverse fetal outcomes, and congenital brain/ocular abnormalities. To ensure successful viral replication, ZIKV manipulates host cell pathways, metabolism, cell proliferation, and immune responses. Kinases, well-established targets in drug discovery, regulate crucial cellular processes, making them ideal therapeutic targets for inhibitory chemical compounds. Due to the highly conserved nature of kinase ATP binding sites, many kinases often bind nonspecifically to inhibitors. This underscores the need to identify highly specific inhibitors through rigorous drug screening processes that additionally identify key pathways in ZIKV infection. Similarly, another viral infection strategy includes altering host lipid metabolism by remodeling intracellular membrane structures. This suggests that metabolite screening may also function to identify metabolites with maximum inhibitory capacity with antiviral effects in ZIKV-infected cells. Upon testing, reduction of ZIKV-induced cytopathic effects, drug clusters around receptor tyrosine kinases and cytosolic kinases, and prevention of viral entry provides proof of competence of the metabolite and kinase screening approach.
INNOVATION: UCLA researchers have developed a method to identify compounds that inhibit host factors crucial in regulating the Zika virus’s replication and response. Researchers screened kinase inhibitors and metabolites to assess their antiviral effects. The research team conducted a primary screen of ~2750 kinase inhibitors to identify compounds that inhibited ZIKV cytopathic effects in RPE cells, then further screened identified hits in a secondary screen in ARPE-19 cells to identify 21 effective kinase inhibitors. They further screened 1050 metabolites and identified 54 with antiviral effects. These screens allowed them to construct drug-protein interaction network maps that revealed cellular pathways that hold potential to block ZIKV replication and prevent cell death. These findings provide a multitude of potential therapeutic compounds and strategies to prevent and treat ZIKV infection to improve treatment outcomes.
POTENTIAL APPLICATIONS:
- Prevention of viral entry and replication in Zika virus infection
- Treatment towards congenital Zika syndrome, systemic infection as well as preventing Zika-mediated Guillain-Barré syndrome (GBS)
ADVANTAGES:
- Kinases are already highly studied, with 46 drugs are currently approved by the FDA
- Many targets and pathways were identified (including metabolites and kinase inhibitors), providing potential for multi-pronged or orthogonal approaches to inhibiting ZIKV
DEVELOPMENT-TO-DATE: Using in vitro screens, researchers identified 21 kinase inhibitors and 54 metabolites that inhibit ZIKV cytopathic effects. Compounds with antiviral activity against Zika virus are validated in preclinical mouse model.
Keywords: Zika virus, ZIKV, kinase, metabolite, screening, RPE, antiviral effects, retinal pigment epithelial cells, kinase inhibitor, drug screen, CPE, ZIKV replication, kinase inhibition, human metabolite library, cell injury