Rocaglamide and silvestrol: a long story from anti-tumor to anti-coronavirus compounds

Schulz, Göran; Victoria, Catherine; Kirschning, Andreas; Steinmann, Eike

doi:10.1039/d0np00024h

Cited by 38 publications

(39 citation statements)

References 34 publications

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“…Among the host factors known to be required for the replication of a broad-spectrum of viruses, eIF4A stands out as one of the most promising targets. Additionally, rocaglates are increasingly being recognized as some of the most promising broad-spectrum antiviral compounds modulating the activity of eIF4A [ 24 , 93 ]. However, the development of such compounds, from basic and preclinical research to clinical studies and commercialization, involves a number of experimental, monetary, clinical, manufacturing, and regulatory challenges.…”

Section: A Pan-antiviral Translational Roadmap For Rocaglatesmentioning

confidence: 99%

“…Recent advances in the development of compounds to target the cellular, cap-dependent DEAD-box RNA helicase eIF4A, an essential factor in viral protein synthesis, have underscored the potential of targeting this translational host factor as an antiviral strategy [ 24 ]. A large number of RNA viruses depend on eIF4A to translate their mRNAs because the complex structure of their 5′ untranslated regions (5′UTRs) requires the helicase activity of eIF4A to form the 43S-preinitiation complex (43S-PIC) during translation initiation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: A Pan-antiviral Translational Roadmap For Rocaglatesmentioning

confidence: 99%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…Among the host factors known to be required for the replication of a broad-spectrum of viruses, eIF4A stands out as one of the most promising targets. Also, rocaglates are increasingly being recognized as some of the most promising broad-spectrum antiviral compounds modulating the activity of eIF4A [20,103]. However, the development of such compounds, from basic and preclinical research to clinical studies and commercialization, involves a number of experimental, monetary, clinical, manufacturing and regulatory challenges.…”

Section: A Pan-antiviral Translational Roadmap For Rocaglatesmentioning

confidence: 99%

“…Recent advances in the development of compounds to target the cellular, cap-dependent DEAD-box RNA helicase eIF4A, an essential factor in viral protein synthesis, have underscored the potential of targeting this translational host factor as an antiviral strategy [20]. A large number of RNA viruses depend on eIF4A to translate their mRNAs because the complex structure of their 5'-untranslated regions (5'UTRs) requires the helicase activity of eIF4A to form the 43S-preinitiation complex (43S-PIC) during translation initiation [21].…”

Section: Introductionmentioning

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

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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’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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“…As a consequence, apart from ongoing screenings for insecticidal properties, there has also been a great parallel interest in that class of compounds as potential anticancer agents (Ohse et al 1996;Wu et al 1997;Cui et al 1997;Lee et al 1998;Bohnenstengel et al 1999a,b;Wang and Duh 2001;Hausott et al 2004;Mi et al 2006a;Zhu et al 2007Zhu et al , 2009Cencic et al 2009;Ribeiro et al 2012;Basmadjian et al 2013). Moreover, anti-inflammatory (Baumann et al 2002;Proksch et al 2005;Fahrig et al 2005;Salim et al 2007b), antiprotozoal (Phongmaykin et al 2011;Astelbauer et al 2011Astelbauer et al , 2012Langlais et al 2018;Drinić et al 2019), and more recently, antiviral activities (Biedenkopf et al 2017;Müller et al 2018Müller et al , 2020Müller et al , 2021Todt et al 2018;Glitscher et al 2018;Elgner et al 2018;Henss et al 2018;Schulz et al 2021;Taroncher-Oldenburg et al 2021) were also reported which greatly stimulated further research in this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Greger

2021

Phytochem Rev

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Flavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure–activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

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Rocaglamide and silvestrol: a long story from anti-tumor to anti-coronavirus compounds

Abstract: The flavagline silvestrol is a potential candidate against viral infections including COVID-19.

Cited by 38 publications

References 34 publications

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

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

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

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