Dataset Information

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

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 a new 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. 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.

INSTRUMENT(S): Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Dengue Virus

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Dengue Hemorrhagic Fever,Dengue Disease,Dengue Shock Syndrome

SUBMITTER: Jonathan Davies

LAB HEAD: Lars Plate

PROVIDER: PXD022453 | Pride | 2021-01-18

REPOSITORIES: Pride

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

Almasy Katherine M KM Davies Jonathan P JP Lisy Samantha M SM Tirgar Reyhaneh R Tran Sirena C SC Plate Lars L

Proceedings of the National Academy of Sciences of the United States of America 20210101 3

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 infectio ...[more]

PMID: 33441483

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Project description:Viruses often induce a complex rewiring of cellular physiology to maximize their propagation. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expresses high amounts of the viral antagonistic protein Orf9b. Increased amounts and mutated versions of Orf9b were found to correlate with improved transmission of more evolved virus forms such as the Alpha and Omicron variants. Orf9b binds to the mitochondrial surface receptor Tom70 which stiffens its highly flexible structure. Tom70 plays a critical role in the antiviral response since it serves as recruiting factor for the mitochondrial antiviral signaling (MAVS) protein. However, the predominant and MAVS-independent role of Tom70 is that of a receptor component of the mitochondrial import system. Whether Orf9b also interferes with this predominant function of Tom70 is unknown. In this study, we expressed Orf9b in human HEK293 cells and observed the Orf9b-mediated depletion of mitochondrial proteins, particularly in respiring cells. The spectrum of depleted mitochondrial proteins was comparable to that of cells in which Tom70 was depleted, consistent with an Orf9b-mediated impairment of Tom70-dependent protein import. To exclude that the observed depletion was caused by the antiviral response triggered by Orf9b expression, we generated a yeast system in which the yeast Tom70 was replaced by a humanized version of Tom70. Upon expression of Orf9b in these cells, we again observed a general but moderate reduction of mitochondrial proteins. Similar to the situation in human cells, a number of mitochondrial proteins were particular sensitive to Orf9b expression, suggesting a rather specific modulation of the mitochondrial import system. In vitro import experiments with semi-intact cells confirmed this Orf9b-mediated impairment of the mitochondrial protein import. Thus, the SARS-CoV-2 virus seems to modulate the mitochondrial proteome by a direct effect of Orf9b on mitochondrial Tom70-dependent protein import.

Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the ï¡-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Experiment Overall Design: 12 mice were analyzed in this study. Four treatment groups were included in this study: transgenic ATF6-MER mice treated with tamoxifen, transgenic ATF6-MER mice treated with vehicle, nontransgenic littermates treated with tamoxifen, and nontransgenic littermates treated with vehicle. Each treatment group included 3 separate biological replicate samples. Each mouse sampled was male, C57/BL6, ~30 weeks old. Each mouse was treated, then the mouse was sacrificed, the heart was extracted, and left ventricle was isolated. Total RNA was isolated from the left ventricle, and used for hybridization onto an Affymetrix mus 430 2.0 full-genome chip. Each heart was hybridized onto its own chip.

Dataset Information

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

Publications

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

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