Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections

Abstract

Significance Viral infections continue to pose a grave global health threat, necessitating the development of new broadly applicable therapeutic strategies, including the targeting of conserved host processes that are exploited during viral infections. Flaviviruses, such as dengue and Zika, depend on extensive engagement of the endoplasmic reticulum (ER) proteostasis network to aid with replication, production, and secretion of virions. Here, we identify a host-centered antiviral approach by targeting these conserved ER protein quality-control processes that are required for viral infection. We find that the small-molecule regulator of ER proteostasis 147 can broadly and safely inhibit dengue and Zika infection without inducing toxicity to the host cells. Flaviviruses, including dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish an additional activity of compound 147 as an effective host-centered antiviral agent against flaviviruses. Compound 147 reduces infection by attenuating the infectivity of secreted virions without causing toxicity in host cells. Compound 147 is a preferential activator of the ATF6 pathway of the ER 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 and additional non-PDI targets using RNAi and other small-molecule inhibitors was unable to recapitulate the antiviral effects, suggesting a unique polypharmacology 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.