The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

Antiviral Res. 2018 Dec;160:38-47. doi: 10.1016/j.antiviral.2018.10.007. Epub 2018 Oct 13.

Abstract

Zika virus (ZIKV) is a human-pathogenic flavivirus that has recently emerged as a global public health threat. ZIKV infection may be associated with congenital malformations in infected fetuses and severe neurological and systemic complications in infected adults. There are currently limited treatment options for ZIKV infection. AR-12 (OSU-03012) is a celecoxib derivative cellular kinase inhibitor that has broad-spectrum antiviral activities. In this study, we investigated the antiviral activity and mechanism of AR-12 against ZIKV. We evaluated the in vitro anti-ZIKV activity of AR-12, using cell protection and virus yield reduction assays, in multiple clinically relevant cell lines, and the in vivo treatment effects of AR-12 in a lethal mouse model using type I interferon receptor-deficient A129 mice. AR-12 inhibited ZIKV strains belonging to both the African and Asian/American lineages in Huh-7 and/or neuronal cells. AR12's IC50 against ZIKV was consistently <2 μM in these cells. ZIKV-infected A129 mice treated with intraperitoneally or orally administered AR-12 had significantly higher survival rate (50.0%-83.3% vs 0%, P < 0.05), less body weight loss, and lower blood and tissue ZIKV RNA loads than untreated control A129 mice. These anti-ZIKV effects were likely the results of down-regulation of the PI3K/Akt pathway by AR-12. Clinical trials using the clinically available and broad-spectrum AR-12 as an empirical treatment should be considered especially for patients residing in or returning from areas endemic of ZIKV and other arboviral infections who present with an acute undifferentiated febrile illness.

Keywords: AR-12; Antiviral; Flavivirus; Inhibitor; Kinase; Zika.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Injections, Intraperitoneal
  • Mice
  • Microbial Sensitivity Tests
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Survival Analysis
  • Treatment Outcome
  • Viral Load
  • Zika Virus / drug effects*
  • Zika Virus / growth & development
  • Zika Virus Infection / pathology
  • Zika Virus Infection / prevention & control*
  • Zika Virus Infection / virology

Substances

  • Antiviral Agents
  • OSU 03012
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Sulfonamides