RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X

Yang, Sundy N. Y.; Atkinson, Sarah C.; Audsley, Michelle D.; Heaton, Steven M.; Jans, David A.; Borg, Natalie A.

doi:10.3390/cells9010170

Cited by 32 publications

(40 citation statements)

References 39 publications

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“…Prompted by these results, we assessed if DDX3X is required for SARS-CoV-2 infection by using two specific inhibitors of DDX3X, the diazepine derivative RK-33 ( Yang et al, 2020 ) and the rhodanine Compound 4B (C-4B) ( Maga et al, 2011 ) ( Figure 4 A). Vero E6 cells were infected with SARS-CoV-2 at MOI 0.001 for 1 hour followed by incubation with the RK-33 or C-4B compounds for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection

et al. 2021

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COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2α phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.

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Section: Resultsmentioning

confidence: 99%

Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection

et al. 2021

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“…In addition, during the late stages of infection, DENV down-regulates DDX3 expression to facilitate viral replication [75]. However, treatment with the DDX3 inhibitor RK-33 reduces DENV replication, suggesting that DDX3 promotes viral replication [76,77]. Furthermore, some evidence showed that DDX3 interacts with the calcium channel TRPV4 to facilitate viral replication of DENV and ZIKV [78].…”

Section: Flaviviruses and Hepacivirusmentioning

confidence: 99%

RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling

2021

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DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses.

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“…Two inhibitors of DDX3X have recently been reported [171,172]. RK-33 is a ring-expanded nucleoside that directly interacts with DDX3X and inhibits its ATPase and helicase activity.…”

Section: Targeting Ddx/dhx-box Helicases In Translation Initiationmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

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DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation.

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RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X

Cited by 32 publications

References 39 publications

Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection

Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection

RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

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