Jumari Snyman, University of Alberta

Jumari Snyman, Eileen Reklow, Manira Gautam, Zaikun Xu, Tom C Hobman: Department Cell Biology, University of Alberta, Edmonton

Fighting & Responding

Emerging and re-emerging RNA viruses continue to threaten global public health, yet for many of these pathogens there are limited or no effective antiviral therapies. The development of broad-spectrum antivirals that target host pathways essential for viral replication represents a promising strategy to address this gap. Peroxisomes are increasingly recognized as important regulators of innate antiviral signaling, including type I interferon responses. Here, we investigated the Wnt/β‑catenin pathway as a potential target to enhance peroxisome biogenesis and promote antiviral activity by modulating the tankyrase regulatory node. Using a Peroxi_SPY650 fluorescent probe in a high-throughput assay, we screened a library of 600 tankyrase inhibitors to identify compounds capable of upregulating peroxisome biogenesis, quantified by total peroxisomal intensity. Thirty compounds increased peroxisome density up to 88% compared to controls. These candidates were subsequently evaluated for antiviral activity against multiple RNA viruses. Viral titration assays demonstrated that several compounds reduced viral replication across multiple viruses, including Influenza A virus, Jamestown Canyon virus, Respiratory Syncytial virus (RSV), and SARS-CoV-2. Treatment with the inhibitors increased type I interferon (IFNβ and IFNλ2) expression following Sendai virus infection, consistent with enhanced innate immune activation. No cytotoxicity was observed in A549, N2a, MDCK, or Calu-3 cells for any of the compounds tested, except for one compound that exhibited cytotoxicity at the highest concentration evaluated (10 µM). These findings identify tankyrase inhibition as a novel strategy to enhance peroxisome-dependent antiviral responses in four distinct viral families and highlight candidate compounds with potential broad-spectrum antiviral activity.