Abstract
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.
Highlights
The frequency of infectious disease outbreaks caused by RNA viruses of zoonotic origin in human populations has been rising at an alarming rate in recent years
Of DEAD-box RNA helicases [49], is an evolutionarily ancient and highly conserved enzyme, the widespread occurrence of chemically diverse eIF4A inhibitors across eukaryal of 19 supergroups suggests that the potential to interfere with eIF4A activity evolved 8independently as an advantageous antagonistic principle in eukaryal evolution (Figure 3)
DDX3, the second DEAD-box RNA helicase targeted by rocaglates [94], interacts with
Summary
The frequency of infectious disease outbreaks caused by RNA viruses of zoonotic origin in human populations has been rising at an alarming rate in recent years. Given the disproportionate contribution of RNA viruses to human infectious disease of zoonotic origin and their dominant role in causing major epidemics and pandemics over the past 20 years, developing antiviral therapeutics targeting RNA viruses should be a priority in the quest to curb the spread of future emerging and re-emerging RNA virus outbreaks. The biggest drawback of direct-targeting antivirals has been the high selective pressure they exert on the RNA viruses themselves This results in enhanced mutation rates and translates into unpredictable “moving goalposts” for drug development and, in more extreme cases, gives rise to escape mutants that can render antivirals altogether ineffective over time [13,14,15]. The potential broad-spectrum application of host-specific translational inhibitors is a crucial argument for their development Such pan-antivirals could be deployed as first-line drugs in the event of an epidemic or pandemic outbreak caused by a novel virus for which there are no direct-targeting antivirals available. Our ability to reduce the widespread and damaging effects of future epidemics and pandemics will greatly benefit from having access to pan-antiviral drugs that can help manage the initial phases of an outbreak
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
