Investigation of a squaramide motif as a bioisostere of the amino-acid group of S-adenosyl-L-methionine and its functional impact on RNA methylation
Bibliographic record
Abstract
Methyltransferases (MTases) are enzymes that methylate biomolecules like proteins, DNA, RNA, lipids, and small molecules, mostly using S-adenosyl-L-methionine (SAM) as a methyl donor. MTases have emerged as promising drug targets, and SAM analogues are widely employed to investigate their involvement in diseases and to develop effective drug therapies. We designed and synthesized stable SAM analogues with a squaramide moiety mimicking the methionine side chain. These compounds were tested on the two human m⁶A RNA MTases METTL3/14 and METTL16. While these SAM analogues failed to support catalytic activity, they exhibited potent inhibitory effects on the METTL3/14 activity. Surprisingly, some of these compounds demonstrated remarkable potency (KI = 3 nM) and specificity, likely attributed to the unique properties of the squaramide motif. Docking studies showed they bind METTL3/14 cofactor pocket similarly to SAM, allowing us to make new hypothesis on the catalytic mechanism. Our synthetic method expands the structural diversity of SAM analogues, providing a foundation for developing selective RNA MTase inhibitors. SAM-dependent methyltransferases (MTases) are crucial enzymes involved in various biological processes and are considered promising drug targets. Here, the authors synthesize SAM analogues with a squaramide moiety mimicking the methionine side chain, demonstrating potent and specific inhibitory effects on RNA MTase METTL3/14 activity.
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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".