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

Katherine M. Almasy; Jonathan P. Davies; Samantha M. Lisy; Reyhaneh Tirgar; Sirena C. Tran; Lars Plate

doi:10.1073/pnas.2012209118

New Research In

Edited by Gaya K. Amarasinghe, Washington University School of Medicine, St. Louis, MO, and accepted by Editorial Board Member Michael F. Summers December 7, 2020 (received for review June 12, 2020)

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.

Abstract

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.

Footnotes

↵¹To whom correspondence may be addressed. Email: lars.plate{at}vanderbilt.edu.

Author contributions: K.M.A. and L.P. designed research; K.M.A., J.P.D., S.M.L., R.T., S.C.T., and L.P. performed research; K.M.A., J.P.D., and L.P. analyzed data; and K.M.A., J.P.D., and L.P. wrote the paper.
Competing interest statement: L.P. is an inventor on a patent (WO2017117430A1) related to the use of 147 for treating protein misfolding diseases.
This article is a PNAS Direct Submission. G.K.A. is a guest editor invited by the Editorial Board.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2012209118/-/DCSupplemental.

Data Availability.

Processed proteomics data are included in Datasets S1–S3. The full mass spectrometry proteomics datasets have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD022453. Extended materials and methods can be found in SI Appendix.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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