Synthesis of long and functionally active RNAs facilitated by acetal levulinic ester chemistry
Bibliographic record
Abstract
Recent advances in RNA-based therapeutics have created a demand for synthetic RNAs that are 100 nucleotides (nts) or longer. In this study, we present the use of 2'-acetal levulinic ester (2'-ALE) phosphoramidites for the synthesis of long RNAs that are at least 215 nts in length. We have developed protocols for rapid (2-4 min) and efficient coupling (>99%) of 2'-ALE monomers and established a rapid, on-column deprotection of RNA strands requiring short alkylamine treatments at room temperature. The results of these studies enabled the successful syntheses of sgRNAs (99 nt), sgRNA tagged with fluorogenic Mango II and Broccoli aptamers (130-170 nt), and 5'-capped minimal mRNAs (200-215 nt), each exhibiting robust functional activity in both cell-free and cellular systems. We also found that the incorporation of 2'-O-methyl-adenosine in the poly(A) tail of synthetic mRNAs markedly enhanced protein expression, highlighting the ALE platform's compatibility for systematic exploration of RNA chemical diversity. Collectively, these results establish 2'-ALE chemistry as a promising platform for the synthesis of long and functionally active RNAs.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".