Dengue and Zika virus infection are impaired by small molecule ER proteostasis regulator 147 in an ATF6-independent manner

Flaviviruses, including Dengue and Zika, are widespread human pathogens, however, no broadly active therapeutics exist to fight infection. Here, we establish the recently discovered pharmacologic modulator of ER proteostasis 147 as an effective host-centered antiviral strategy. Compound 147 reduces infection by attenuating viral replication without causing toxicity in host cells. 147 is a preferential activator of the ATF6 pathway of the unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs using RNAi and other PDI small molecule inhibitors was unable to recapitulate the antiviral effects, suggesting additional identified protein targets of 147 may mediate the activity. Importantly, 147 can impair infection of multiple strains of Dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent.