Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation

  • Antiviral Res. 2019 Nov:171:104598. doi: 10.1016/j.antiviral.2019.104598.
Xianting Ding  1 ,  Peter O Krutzik  2 ,  Amir Ali Ghaffari  3 ,  Yixiu Zhaozhi  1 ,  Daniel Miranda Jr  4 ,  Genhong Cheng  3 ,  Chih-Ming Ho  5 ,  Garry P Nolan  2 ,  David Jesse Sanchez  6
Affiliations
  • 1. Institute for Personalized Medicine, State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, PR China.
  • 2. Microbiology & Immunology - Baxter Laboratory, Stanford University, Palo Alto, CA, USA.
  • 3. Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA.
  • 4. Pharmaceutical Sciences Department, Western University of Health Sciences, Pomona, CA, USA.
  • 5. Mechanical and Aerospace Engineering Department, School of Engineering and Applied Science, University of California, Los Angeles, CA, USA.
  • 6. Pharmaceutical Sciences Department, Western University of Health Sciences, Pomona, CA, USA. Electronic address: [email protected].
PMID: 31513822 DOI: 10.1016/j.antiviral.2019.104598
Abstract

As Antiviral drug resistance develops and new viruses emerge there is a pressing need to develop strategies to rapidly develop Antiviral therapeutics. Here we use phospho-specific flow cytometry to assess perturbations of many different cellular signaling pathways during treatment with drug combinations that are highly effective in blocking Herpes simplex virus type 1 (HSV-1) Infection. We discovered two Antiviral drug combinations act on distinct signaling pathways, either STAT1 or S6 phosphorylation, to block HSV-1 Infection. We focused on upregulation of S6 phosphorylation by HSV-1 Infection, and our subsequent finding that ribavirin antagonizes this upregulation of S6 phosphorylation. We go on to show that the S6 kinase inhibitor SL0101 blocks HSV-1 replication in vitro and in an in vivo animal model of HSV-1 Infection. Overall, we have used an unbiased analysis of cellular signaling pathways during treatment by Antiviral drug combinations to discover a novel Antiviral drug target against HSV-1 Infection. The outcomes of the approach we present highlight the importance of analyzing how Antiviral drugs modulate cellular and pathogen-induced signaling as a method to discover new drug therapy targets.