Targeting host DEAD-box RNA helicase DDX3X for treating viral infections

Winnard, Paul T.; Vesuna, Farhad; Raman, Venu

doi:10.1016/j.antiviral.2020.104994

Cited by 25 publications

(20 citation statements)

References 87 publications

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“…This is probably because at the molecular level SARS-CoV-2 usurps DDX3 in the host cell to its advantage for replication and for pathogenesis. This is in parallel to what is already demonstrated by many other viruses that utilize DDX3 for viral entry, processing, and egress from the host cells 57 . Furthermore, as DDX3 has been shown to interact with nucleocapsid protein of SARS-CoV-2 54 , it is plausible that the use of RK-33 is directly interfering with SARS-CoV-2 replication machinery as well.…”

Section: Discussionsupporting

confidence: 82%

RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

Vesuna

Akhrymuk

Smith

et al. 2022

Preprint

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SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy towards them is waning. As a result, SARS-CoV-2 will continue to have a deadly impact on public health into the foreseeable future. One strategy to bypass the continuing problem of newer variants is to target host proteins required for viral replication. We have used this host-targeted antiviral (HTA) strategy that targets DDX3, a host DEAD-box RNA helicase that is usurped by SARS-CoV-2 for virus production. We demonstrated that targeting DDX3 with RK-33, a small molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by one to three log orders in Calu-3 cells. Furthermore, proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we show that the use of RK-33 decreases TMPRSS2 expression, which may be due to DDX3s ability to unwind G-quadraplex structures present in the TMPRSS2 promoter. The data presented supports the use of RK-33 as an HTA strategy to control SARS-CoV-2 infection, irrespective of its mutational status, in humans.

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Section: Discussionsupporting

confidence: 82%

RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

Vesuna

Akhrymuk

Smith

et al. 2022

Preprint

Self Cite

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“…Given its multifaceted functions during replication of several viruses, DDX3 emerges as a promising target for the development of broad-spectrum antivirals [77,[127][128][129]. Indeed, many different small molecules capable of inhibiting DDX3 enzymatic activities have been developed and evaluated as antiviral molecules [77,[130][131][132].…”

Section: Ddx3 As a Promising Broad-spectrum Antiviral Targetmentioning

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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“…The ATP-dependent RNA helicase DEAD-box helicase 3 X (DDX3X) is involved in cellular processes that are different from those involved in innate immunity. DDX3X is required for the replication of many viruses including HCV (He et al, 2021;Winnard et al, 2021). DDX3X has been shown to colocalize with LD, HCV core and NS proteins.…”

Section: Hcv and Denv/zikv Hijack The Srebp Pathway To Accomplish Vir...mentioning

confidence: 99%

Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions

Kaiser

Romano

Vanrell

et al. 2022

Front. Cell Dev. Biol.

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Lipid droplets (LD) have long been considered as mere fat drops; however, LD have lately been revealed to be ubiquitous, dynamic and to be present in diverse organelles in which they have a wide range of key functions. Although incompletely understood, the biogenesis of eukaryotic LD initiates with the synthesis of neutral lipids (NL) by enzymes located in the endoplasmic reticulum (ER). The accumulation of NL leads to their segregation into nanometric nuclei which then grow into lenses between the ER leaflets as they are further filled with NL. The lipid composition and interfacial tensions of both ER and the lenses modulate their shape which, together with specific ER proteins, determine the proneness of LD to bud from the ER toward the cytoplasm. The most important function of LD is the buffering of energy. But far beyond this, LD are actively integrated into physiological processes, such as lipid metabolism, control of protein homeostasis, sequestration of toxic lipid metabolic intermediates, protection from stress, and proliferation of tumours. Besides, LD may serve as platforms for pathogen replication and defense. To accomplish these functions, from biogenesis to breakdown, eukaryotic LD have developed mechanisms to travel within the cytoplasm and to establish contact with other organelles. When nutrient deprivation occurs, LD undergo breakdown (lipolysis), which begins with the LD-associated members of the perilipins family PLIN2 and PLIN3 chaperone-mediated autophagy degradation (CMA), a specific type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes. Indeed, PLINs CMA degradation is a prerequisite for further true lipolysis, which occurs via cytosolic lipases or by lysosome luminal lipases when autophagosomes engulf portions of LD and target them to lysosomes. LD play a crucial role in several pathophysiological processes. Increased accumulation of LD in non-adipose cells is commonly observed in numerous infectious diseases caused by intracellular pathogens including viral, bacterial, and parasite infections, and is gradually recognized as a prominent characteristic in a variety of cancers. This review discusses current evidence related to the modulation of LD biogenesis and breakdown caused by intracellular pathogens and cancer.

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Targeting host DEAD-box RNA helicase DDX3X for treating viral infections

Cited by 25 publications

References 87 publications

RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

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

Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions

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