Effect of Sugar 2′,4′-Modifications on Gene Silencing Activity of siRNA Duplexes
Bibliographic record
Abstract
In this study, we explore the effect of a library of 2′-, 4′-, and 2′,4′-modified uridine nucleosides and their impact on silencing firefly luciferase and on down-regulated in renal cell carcinoma (DRR) gene targets. The modifications studied were 2′-F-ribose, 2′-F-arabinose, 2′-OMe-ribose, 2′-F,4′-OMe-ribose, 2′-F,4′-OMe-arabinose, and 2′-OMe,4′-F-ribose. We found that 2′,4′-modifications are well tolerated within A-form RNA duplexes, leading to virtually no change in melting temperature as assessed by UV thermal melting. The impact of the dual (2′,4′) modification was assessed by comparing gene silencing ability to 2′- or 4′- (singly) modified siRNA counterparts. siRNAs with (2′,4′)-modified overhangs generally outperformed the native siRNA as well as siRNAs with a 2′- or 4′-modified overhang, suggesting that 2′,4′-modified nucleotides interact favorably with Argonaute protein's PAZ domain. Among the most active siRNAs were those with 2′-F,4′-OMe-ribose or 2′-F,4′-OMe-arabinose at the overhangs. When modifications were placed at both overhangs and internal positions, a duplex with the 2′-F (internal) and 2′-F,4′-OMe (overhang) combination was found to be the most potent, followed by the duplex with 2′-OMe (internal) and 2′,4′-diOMe (overhang) modifications. Given the nuclease resistance exhibited by 2′,4′-modified siRNAs, particularly when the modification is placed at or near the overhangs, these findings may allow the creation of superior siRNAs for therapy.
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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 | 0.000 |
| 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".