Discovery and characterization of novel inhibitors of protein kinase R
Bibliographic record
Abstract
Double-stranded RNA-dependent protein kinase (PKR) is an interferon-inducible serine/threonine kinase that plays a crucial role in innate immunity against viral infections. Activated PKR downregulates global protein synthesis through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2) and induces transcriptional output of cellular mRNAs implicated in limiting viral spread. Accumulating evidence suggests that PKR is involved in a multitude of other cellular processes including signal transduction, apoptosis, cell growth and differentiation, as well as the pathogenesis of several neurodegenerative diseases. In this context, small molecules targeting PKR would be useful as tools to help understand the intricacies of such biological pathways. In screening a library of natural and synthetic products for eukaryotic translation modulators, we identified two small molecules, isohymenialdisine and hymenialdisine, that exhibit stimulatory effects on translation. Characterization of the mode of action of isohymenialdisine revealed that it directly acts on PKR by inhibiting its autophosphorylation activity and perturbs the PKR-eIF2α phosphorylation axis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".