2. Academic Validation
  3. Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses

Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses

  • Viruses. 2023 Feb 28;15(3):655. doi: 10.3390/v15030655.
Niloufar A Boghdeh 1,  Brittany McGraw 2,  Michael D Barrera 1 2,  Carol Anderson 1 2,  Haseebullah Baha 1 2,  Kenneth H Risner 1 2,  Ifedayo V Ogungbe 3,  Farhang Alem 1 2,  Aarthi Narayanan 1 4
Affiliations

Affiliations

  • 1 Biomedical Research Laboratory, George Mason University, Manassas, VA 20110, USA.
  • 2 School of Systems Biology, College of Science, George Mason University, Manassas, VA 20110, USA.
  • 3 Department of Chemistry, Physics and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA.
  • 4 Department of Biology, College of Science, George Mason University, Fairfax, VA 22030, USA.
PMID: 36992362 DOI: 10.3390/v15030655
Abstract

New World alphaviruses including Venezuelan Equine Encephalitis Virus (VEEV) and Eastern Equine Encephalitis Virus (EEEV) are mosquito-transmitted viruses that cause disease in humans and equines. There are currently no FDA-approved therapeutics or vaccines to treat or prevent exposure-associated encephalitic disease. The ubiquitin Proteasome system (UPS)-associated signaling events are known to play an important role in the establishment of a productive Infection for several acutely infectious viruses. The critical engagement of the UPS-associated signaling mechanisms by many viruses as host-pathogen interaction hubs led us to hypothesize that small molecule inhibitors that interfere with these signaling pathways will exert broad-spectrum inhibitory activity against alphaviruses. We queried eight inhibitors of the UPS signaling pathway for Antiviral outcomes against VEEV. Three of the tested inhibitors, namely NSC697923 (NSC), bardoxolone methyl (BARM) and omaveloxolone (OMA) demonstrated broad-spectrum Antiviral activity against VEEV and EEEV. Dose dependency and time of addition studies suggest that BARM and OMA exhibit intracellular and post-entry viral inhibition. Cumulatively, our studies indicate that inhibitors of the UPS-associated signaling pathways exert broad-spectrum Antiviral outcomes in the context of VEEV and EEEV Infection, supporting their translational application as therapeutic candidates to treat alphavirus infections.

Keywords

Eastern Equine Encephalitis Virus; Venezuelan Equine Encephalitis Virus; alphavirus; antiinflammatory; antiviral; bardoxolone methyl; omaveloxolone; therapeutics; ubiquitin proteasome system; ubiquitin signaling pathways.

Figures
Products