BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals

• Published in: Antiviral research Vol. 184; p. 104966
• Main Authors: Pu, Szuyuan, Schor, Stanford, Karim, Marwah, Saul, Sirle, Robinson, Makeda, Kumar, Sathish, Prugar, Laura I., Dorosky, Danielle E., Brannan, Jennifer, Dye, John M., Einav, Shirit
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2020
• Subjects: Adaptor Proteins, Vesicular Transport - antagonists & inhibitors; Animals; Antiviral Agents - pharmacology; Antivirals; Cell Line; Chlorocebus aethiops; Dengue - drug therapy; Dengue - virology; Dengue virus; Dengue Virus - drug effects; Dengue Virus - physiology; Drug Repositioning; Drug repurposing; Host Microbial Interactions; Humans; Intracellular Signaling Peptides and Proteins - physiology; Kinase inhibitors; Lactones - pharmacology; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - physiology; Recombinant Proteins; Resorcinols - pharmacology; RNA, Viral; Signal Transduction; Transcription Factors - physiology; Vero Cells; Virus Internalization; Virus Replication; Virus-host interactions; Drug repurposing; Dengue virus; Kinase inhibitors; Virus-host interactions; Antivirals
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2020.104966

Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Here, we reveal a requirement for BIKE, but not STK-16, in dengue virus (DENV) infection. BIKE mediates both early (postinternalization) and late (assembly/egress) stages in the DENV life cycle, and this effect is mediated in part by phosphorylation of a threonine 156 (T156) residue in the μ subunit of the adaptor protein (AP) 2 complex. Pharmacological compounds with potent anti-BIKE activity, including the investigational anticancer drug 5Z-7-oxozeaenol and more selective inhibitors, suppress DENV infection both in vitro and ex vivo. BIKE overexpression reverses the antiviral activity, validating that the mechanism of antiviral action is, at least in part, mediated by BIKE. Lastly, 5Z-7-oxozeaenol exhibits antiviral activity against viruses from three unrelated RNA viral families with a high genetic barrier to resistance. These findings reveal regulation of poorly understood stages of the DENV life cycle via BIKE signaling and establish a proof-of-principle that pharmacological inhibition of BIKE can be potentially used as a broad-spectrum strategy against acute emerging viral infections.