Host oxidative folding pathways offer novel anti-chikungunya virus drug targets with broad spectrum potential

Rose Langsjoen, Albert J. Auguste, Shannan Rossi, Christopher M. Roundy, Heidy N. Penate, Maria Kastis, Matthew K. Schnizlein, Kevin C. Le, Sherry L. Haller, Rubing Chen, Stanley Watowich, Scott Weaver

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Alphaviruses require conserved cysteine residues for proper folding and assembly of the E1 and E2 envelope glycoproteins, and likely depend on host protein disulfide isomerase-family enzymes (PDI) to aid in facilitating disulfide bond formation and isomerization in these proteins. Here, we show that in human HEK293 cells, commercially available inhibitors of PDI or modulators thereof (thioredoxin reductase, TRX-R; endoplasmic reticulum oxidoreductin-1, ERO-1) inhibit the replication of CHIKV chikungunya virus (CHIKV) in vitro in a dose-dependent manner. Further, the TRX-R inhibitor auranofin inhibited Venezuelan equine encephalitis virus and the flavivirus Zika virus replication in vitro, while PDI inhibitor 16F16 reduced replication but demonstrated notable toxicity. 16F16 significantly altered the viral genome: plaque-forming unit (PFU) ratio of CHIKV in vitro without affecting relative intracellular viral RNA quantities and inhibited CHIKV E1-induced cell-cell fusion, suggesting that PDI inhibitors alter progeny virion infectivity through altered envelope function. Auranofin also increased the extracellular genome:PFU ratio but decreased the amount of intracellular CHIKV RNA, suggesting an alternative mechanism of action. Finally, auranofin reduced footpad swelling and viremia in the C57BL/6 murine model of CHIKV infection. Our results suggest that targeting oxidative folding pathways represents a potential new anti-alphavirus therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)246-251
Number of pages6
JournalAntiviral Research
Volume143
DOIs
StatePublished - Jul 1 2017

Fingerprint

Chikungunya virus
Protein Disulfide-Isomerases
Auranofin
Alphavirus
Pharmaceutical Preparations
Enzyme Inhibitors
Venezuelan Equine Encephalitis Viruses
Thioredoxin-Disulfide Reductase
Flavivirus
Cell Fusion
Viral Genome
Viremia
Viral RNA
Enzymes
Virus Replication
Endoplasmic Reticulum
Disulfides
Virion
Cysteine
Glycoproteins

Keywords

  • Alphavirus
  • Auranofin
  • Chikungunya virus
  • Protein disulfide isomerase
  • Protein folding
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Host oxidative folding pathways offer novel anti-chikungunya virus drug targets with broad spectrum potential. / Langsjoen, Rose; Auguste, Albert J.; Rossi, Shannan; Roundy, Christopher M.; Penate, Heidy N.; Kastis, Maria; Schnizlein, Matthew K.; Le, Kevin C.; Haller, Sherry L.; Chen, Rubing; Watowich, Stanley; Weaver, Scott.

In: Antiviral Research, Vol. 143, 01.07.2017, p. 246-251.

Research output: Contribution to journalArticle

Langsjoen, Rose ; Auguste, Albert J. ; Rossi, Shannan ; Roundy, Christopher M. ; Penate, Heidy N. ; Kastis, Maria ; Schnizlein, Matthew K. ; Le, Kevin C. ; Haller, Sherry L. ; Chen, Rubing ; Watowich, Stanley ; Weaver, Scott. / Host oxidative folding pathways offer novel anti-chikungunya virus drug targets with broad spectrum potential. In: Antiviral Research. 2017 ; Vol. 143. pp. 246-251.
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