Identification and evaluation of antivirals for Rift Valley fever virus

Authors: LANG, YUEKUN - Kansas State University; LI, YONGHAI - Kansas State University; Jasperson, Dane; HENNINGSON, JAMIE - Kansas State University; LEE, JINHWA - Kansas State University; MA, JINGJIAO - Kansas State University; LI, YUHAO - Kansas State University; DUFF, MICHAEL - Kansas State University; LIU, HAIXIA - Kansas State University; BAI, DINGPING - Kansas State University; McVey, David; RICHT, JUERGEN - Kansas State University; IKEGAMI, TETSURO - University Of Texas Medical Branch; Wilson, William - Bill; MA, WENJUN - Kansas State University

Submitted to: Veterinary Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/28/2019
Publication Date: 2/14/2019
Citation: Lang, Y., Li, Y., Jasperson, D.C., Henningson, J., Lee, J., Ma, J., Li, Y., Duff, M., Liu, H., Bai, D., McVey, D.S., Richt, J., Ikegami, T., Wilson, W.C., Ma, W. 2019. Identification and evaluation of antivirals for Rift Valley fever virus. Veterinary Microbiology. 230:110-116. https://doi.org/10.1016/j.vetmic.2019.01.027.
DOI: https://doi.org/10.1016/j.vetmic.2019.01.027

Interpretive Summary: Rift Valley fever virus is the causative agent not present in the US but poses a significant livestock and human health risk if introduced into the US. There are no license human vaccines and not antiviral treatment for this disease. In this study, over 700 compounds were screened for effectiveness against RVFV. Of these compounds two were identified and further supported as potential therapeutic agents using a mouse RVFV infection model.

Technical Abstract: Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever (RVF) that affects both livestock and humans. There are neither fully licensed RVF vaccines available for human or animal use, nor effective antiviral drugs approved for human use in the U.S. To identify antiviral compounds effective for RVF, we developed and employed a cell-based high-throughput assay using recombinant RVFV MP-12 strain, which expresses Renilla luciferase in place of the NSs protein, to screen 727 small compounds purchased from the National Institutes of Health. Twenty three compounds were primarily identified in the screening. Two compounds including 6-azauridine and mitoxantrone also inhibited the replication of parental MP-12 strain encoding the NSs gene, with limited cytotoxic effects. The respective 50% inhibitory concentrations were 29.07 µM and 79.85 µM when tested with parental MP-12 strain at a multiplicity of infection of 2. The compounds were further evaluated using the STAT-1 KO mouse model. At one hour post intranasal inoculation of MP-12 strain, mice were intranasally treated with each indicated compound twice daily. Mice treated with either placebo or 6-azauridine displayed severe weight loss and reached the threshold for euthanasia with obvious neurologic symptoms. Onset of disease was, however, delayed in mice treated with either ribavirin or mitoxantrone. The results indicated that mitoxantrone can reduce the severity of diseases in RVFV-infected mice. Our studies build the foundation for the initial screening and efficacy trials of RVF antivirals in a BSL-2 environment, avoiding the risks of BSL-3 exposure with wild-type virus.