Mechanistic Insights into Molecular Staples as Potent Inhibitors of DEAD-box RNA Helicases
Bibliographic record
Abstract
DEAD-box RNA (DDX) helicases are the largest family of RNA helicases constituting 37 members.They are involved in all facets of gene expression involving RNA.DDX helicase comprises a highly conserved helicase core with extending N-terminal and C-terminal domains, which determine their activity in controlling gene expression.Dysregulation of DDX helicases is implicated in various cancers.Targeting protein synthesis (mRNA translation) is being considered as a viable anti-cancer strategy especially to resensitize tumors that are resistant to standard-ofcare agents.The limiting step in translation is the initiation phase that involves recruitment of ribosomes on to the start codon of the mRNA.Translation initiation is dependent on the eukaryotic translation initiation factor (eIF)4F, which is a trimeric complex consisting of eIF4E (cap-binding subunit), eIF4G (a large scaffolding protein), and eIF4A (DDX helicase).eIF4A is a prototypical DDX helicase representing the conserved helicase core with minimal extending domains.Mammalians expresses three eIF4A paralogs of which eIF4A1 and eIF4A2 share 90% amino acid identity and are involved in translation initiation, whereas eIF4A3 share 66% amino acid identity with eIF4A1 and is involved in Nonsense-mediated decay (NMD).Two structurally distinct families rocaglates and pateamine A (PatA) are found to target eIF4A1/2 by stabilizing eIF4A-RNA complexes and are called as molecular staples or interfacial inhibitors as they act by stabilizing interaction of two macromolecules.These are found to be potent inhibitors of translation in both in vitro and ex vivo settings and shown to be well tolerated in vivo.Rocaglates clamp eIF4A1 onto purine bases of RNA and preferably inhibit translation of mRNAs containing purine rich 5'UTR with the exception being silvestrol (natural rocaglate), which also inhibits mRNAs containing pyrimidine rich 5'UTRs.Molecular basis of natural rocaglate RocA
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".