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

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.

Comments：

The passage describes a study that investigated the use of small molecule inhibitors that interfere with UPS-associated signaling pathways as potential therapeutic candidates for the treatment of mosquito-transmitted alphaviruses such as VEEV and EEEV, which currently have no approved treatments or vaccines. The study tested eight inhibitors of the UPS signaling pathway against VEEV and found that three of them, NSC697923, bardoxolone methyl, and omaveloxolone, exhibited broad-spectrum antiviral activity against both VEEV and EEEV. Further dose dependency and time of addition studies suggest that bardoxolone methyl and omaveloxolone inhibited viral replication within cells and after viral entry. Overall, the study suggests that these UPS-associated signaling pathway inhibitors could be used as therapeutic candidates for treating alphavirus infections.