Journal
MICROORGANISMS
Volume 9, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/microorganisms9030540
Keywords
pan-antiviral; rocaglates; eIF4A; silvestrol; CR-31-B; Zotatifin; translation initiation; coronavirus; COVID-19
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Funding
- LOEWE Center DRUID
- German Center for Infection Research (DZIF), partner site Giessen-Marburg-Langen (TTU Emerging Infections)
- Deutsche Forschungsgemeinschaft [SFB 1021, CRU KFO309]
- BMBF project HELIATAR
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The study suggests that Rocaglates, a group of compounds from plants, have great potential as broad-spectrum antivirals by limiting the translation of RNA viruses with minimal toxic side effects. Their unique mechanism of action makes them promising candidates for the development of pan-antiviral therapeutics.
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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