The steroid derivative 6-aminocholestanol inhibits the DEAD-box helicase eIF4A (LieIF4A) from the Trypanosomatid parasite Leishmania by perturbing the RNA and ATP binding sites

Abdelkrim, Yosser Zina; Harigua‐Souiai, Emna; Barhoumi, Mourad; Banroques, Josette; Blondel, Arnaud; Tanner, N. Kyle

doi:10.1016/j.molbiopara.2018.10.001

Cited by 18 publications

(29 citation statements)

References 46 publications

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“…Firstly, as far as we can assess, previous studies that identified elatol, elisabatin A, and 6-AC as eIF4A1 inhibitors used the malachite green-based assay to score for inhibition of ATPase activity. The recombinant eIF4A1 preparations used in several of these studies are reported to have been isolated via a single affinity chromatography steptaking advantage of an engineered His 6 tag (Abdelkrim et al 2018;Harigua-Souiai et al 2018;Peters et al 2018). Although the increase in specific activity following immobilized metal-affinity purification (IMAC) can be extremely high, it does not yield protein preparations that are free of contaminants.…”

Section: Resultsmentioning

confidence: 99%

“…The prostaglandin, 15d-PGJ2, has been reported to inhibit translation and when immobilized on a solid support matrix was able to capture eIF4A1 (but not eIF4G1) from cytoplasmic extracts, suggesting that it interferes with eIF4A: eIF4G interaction (Kim et al 2007;Yun et al 2018). The antifungal agent, 6-aminocholestanol (6-AC), was identified following virtual docking simulations as a potential inhibitor of mammalian and Leishmania eIF4A1 (Abdelkrim et al 2018;Harigua-Souiai et al 2018). In vitro testing found that 6-AC blocked the ATPase and helicase activity of mammalian and Leishmania (Li) eIF4A1 (Abdelkrim et al 2018;Harigua-Souiai et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The antifungal agent, 6-aminocholestanol (6-AC), was identified following virtual docking simulations as a potential inhibitor of mammalian and Leishmania eIF4A1 (Abdelkrim et al 2018;Harigua-Souiai et al 2018). In vitro testing found that 6-AC blocked the ATPase and helicase activity of mammalian and Leishmania (Li) eIF4A1 (Abdelkrim et al 2018;Harigua-Souiai et al 2018). Lastly, sanguinarine (SAN) has recently been reported to inhibit eIF4A1 ATPase and helicase activity (Jiang et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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A comparative study of small molecules targeting eIF4A

Naineni

Maïga

Cencic

et al. 2020

RNA

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The PI3K/Akt/mTOR kinase pathway is extensively deregulated in human cancers. One critical node under regulation of this signaling axis is eukaryotic initiation factor (eIF) 4F, a complex involved in the control of translation initiation rates. eIF4F-dependent addictions arise during tumor initiation and maintenance due to increased eIF4F activity-generally in response to elevated PI3K/Akt/mTOR signaling flux. There is thus much interest in exploring eIF4F as a small molecule target for the development of new anticancer drugs. The DEAD-box RNA helicase, eIF4A, is an essential subunit of eIF4F, and several potent small molecules (rocaglates, hippuristanol, pateamine A) affecting its activity have been identified and shown to demonstrate anticancer activity in vitro and in vivo in preclinical models. Recently, a number of new small molecules have been reported as having the capacity to target and inhibit eIF4A. Here, we undertook a comparative analysis of their biological activity and specificity relative to the eIF4A inhibitor, hippuristanol.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A comparative study of small molecules targeting eIF4A

Naineni

Maïga

Cencic

et al. 2020

RNA

View full text Add to dashboard Cite

show abstract

“…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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“…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 [71]. The list includes allolaurinterol, elatol, elisabatin A, 6-aminocholestanol, sanguinarine, and the prostaglandin 15d-PGJ2 [72][73][74][75][76]. Allolaurinterol and elatol are found in red algae and silvestrol and other rocaglates in plants, all within the supergroup Archaeplastida.…”

Section: Figurementioning

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

Preprint

View full text Add to dashboard Cite

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’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.

show abstract

The steroid derivative 6-aminocholestanol inhibits the DEAD-box helicase eIF4A (LieIF4A) from the Trypanosomatid parasite Leishmania by perturbing the RNA and ATP binding sites

Cited by 18 publications

References 46 publications

A comparative study of small molecules targeting eIF4A

A comparative study of small molecules targeting eIF4A

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

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

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