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

• Published in: Viruses Vol. 15; no. 3; p. 655
• Main Authors: Boghdeh, Niloufar A, McGraw, Brittany, Barrera, Michael D, Anderson, Carol, Baha, Haseebullah, Risner, Kenneth H, Ogungbe, Ifedayo V, Alem, Farhang, Narayanan, Aarthi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.02.2023; MDPI
• Subjects: Alphavirus; Animals; Antiviral activity; Antiviral Agents - pharmacology; Control; Dengue fever; Disease transmission; Dose dependency; Eastern equine encephalitis; Eastern Equine Encephalitis Virus; Encephalitis; Encephalitis Virus, Venezuelan Equine; Health aspects; Horses; Humans; Infections; omaveloxolone; Pandemics; Proteasomes; RNA viruses; Signal Transduction; Ubiquitin; ubiquitin proteasome system; ubiquitin signaling pathways; Venezuelan equine encephalitis; Venezuelan Equine Encephalitis Virus; Viral infections; Viruses; United States; United States > US; Venezuelan Equine Encephalitis Virus; therapeutics; Eastern Equine Encephalitis Virus; ubiquitin signaling pathways; antiviral; ubiquitin proteasome system; omaveloxolone; alphavirus; antiinflammatory; bardoxolone methyl
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15030655

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.