Aβ(1-42) Assembly in the Presence of <i>scyllo</i>-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors
Bibliographic record
Abstract
To identify a lead skeleton structure for optimization of scyllo-inositol-based inhibitors of amyloid-beta peptide (Aβ) aggregation, we have synthesized aldoxime, hydroxamate, carbamate, and amide linked scyllo-inositol derivatives. These structures represent backbones that can be readily expanded into a wide array of derivatives. They also provide conservative modifications of the scyllo-inositol backbone, as they maintain the display of the equatorial polar atoms, preserving the stereochemical requirement necessary for maximum inhibition of Aβ(1-42) fiber formation. In addition, a reliable work plan for screening derivatives was developed in order to preferentially identify a backbone(s) structure that prevents fibrillogenesis and stabilizes nontoxic small molecular weight oligomers, as we have previously reported for scyllo-inositol. In the present studies, we have adapted a high throughput ELISA-based oligomerization assay followed by atomic force microscopy to validate the results screen compounds. The lead compounds were then tested for toxicity and ability to rescue Aβ(1-42) induced toxicity in vitro and the affinity of the compounds for Aβ(1-42) compared by mass spectrometry. The data to suggest that compounds must maintain a planar conformation to exhibit activity similar to scyllo-inositol and that the oxime derivative represents the lead backbone for future development.
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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 | 0.000 | 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 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".