Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling

Jiang, Chenxiao; Tang, Yegen; Ding, Lulu; Tan, Renke; Li, Xiaojing; Lu, Junyan; Jiang, Jing; Cui, Zheng; Tang, Zhewei; Li, Wei; Cao, Zhilong; Schneider‐Poetsch, Tilman; Jiang, Wei; Luo, Cheng; Ding, Yu; Liu, Jianwei; Dang, Yongjun

doi:10.1016/j.chembiol.2019.07.010

Cited by 10 publications

(9 citation statements)

References 54 publications

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“…The prostaglandin 15d‐PGJ2, has been reported to bind to eIF4A1 and inhibit eIF4A–eIF4G interaction (Kim et al, 2007; Yun et al, 2018). Also, both 6‐aminocholestanol (6‐AC) and sanguinarine (SAN) were reported to block eIF4A ATPase and helicase activity (Abdelkrim et al, 2018; Harigua‐Souiai et al, 2018; Jiang et al, 2019). Recently, a substituted quinoline analog, cmpd 28, was identified following a screen for inhibitors of eIF4A ATPase activity and found to be an RNA‐competitive, ATP‐uncompetitive inhibitor (Zerio et al, 2021).…”

Section: Small Molecule Inhibitors Of Dead‐box Rna Helicasesmentioning

confidence: 99%

Targeting DEAD‐box RNA helicases: The emergence of molecular staples

et al. 2022

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RNA helicases constitute a large family of proteins that play critical roles in mediating RNA function. They have been implicated in all facets of gene expression pathways involving RNA, from transcription to processing, transport and translation, and storage and decay. There is significant interest in developing small molecule inhibitors to RNA helicases as some family members have been documented to be dysregulated in neurological and neurodevelopment disorders, as well as in cancers. Although different functional properties of RNA helicases offer multiple opportunities for small molecule development, molecular staples have recently come to the forefront. These bifunctional molecules interact with both protein and RNA components to lock them together, thereby imparting novel gain-of-function properties to their targets.

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Section: Small Molecule Inhibitors Of Dead‐box Rna Helicasesmentioning

confidence: 99%

Targeting DEAD‐box RNA helicases: The emergence of molecular staples

et al. 2022

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“…Considering that eIF4A, the prototype In addition to the three best-known classes of eIF4A inhibitors, other low-molecularweight compounds have been shown to inhibit the helicase, although the specificity and selectivity of several of them remains to be established, and their potential antiviral activity has not yet been determined [85]. The list includes allolaurinterol, elatol, elisabatin A, 6-aminocholestanol, sanguinarine, and the prostaglandin 15d-PGJ2 [86][87][88][89][90]. Allolaurinterol and elatol are found in red algae and silvestrol and other rocaglates in plants, all within the supergroup Archaeplastida.…”

Section: Eif4a Inhibitorsmentioning

confidence: 99%

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates—A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

Taroncher-Oldenburg¹,

Müller

Obermann

et al. 2021

Microorganisms

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The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5′ untranslated regions (5′UTRs) onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5′UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

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“…eIF4A is a dumbell-shaped protein which features two RecA-like domains joined by an intermediate, flexible linker [24,25]. Conserved motifs line these domains and contribute to mRNA and ATP binding (Figure S1.)…”

Section: Statement Of Significancementioning

confidence: 99%

Mapping the interaction between eukaryotic initiation factor 4A (eIF4A) and the inhibitor hippuristanol using carbene footprinting and mass spectrometry

et al. 2021

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Protein-ligand interactions are central to protein activity and cell functionality.Improved knowledge of these relationships greatly benefits our understanding of key biological processes and aids in rational drug design towards the treatment of clinically relevant diseases. Carbene footprinting is a recently developed mass spectrometrybased chemical labelling technique that provides valuable information relating to protein-ligand interactions, such as the mapping of binding sites and associated conformational change. Here, we show the application of carbene footprinting to the interaction between eIF4A helicase and a natural product inhibitor, hippuristanol, found in the coral Isis hippuris. Upon addition of hippuristanol we identified reduced carbene labelling (masking) in regions of eIF4A previously implicated in ligand binding. Additionally, we detected hippuristanol-associated increased carbene labelling (unmasking) around the flexible hinge region of eIF4A, indicating ligand-induced conformational change. This work represents further development of the carbene footprinting technique and demonstrates its potential in characterising medicinally relevant proteinligand interactions.

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Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling

Cited by 10 publications

References 54 publications

Targeting DEAD‐box RNA helicases: The emergence of molecular staples

Targeting DEAD‐box RNA helicases: The emergence of molecular staples

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates—A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

Mapping the interaction between eukaryotic initiation factor 4A (eIF4A) and the inhibitor hippuristanol using carbene footprinting and mass spectrometry

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