P4‐220: DEVELOPMENT OF TRYPTOPHAN‐BASED BETA‐AMYLOID ANTI‐AGGREGANTS
Bibliographic record
Abstract
As part of our ongoing search to identify “endogenous anti-Alzheimer's molecules” within the human brain we have focussed on indoleamine-2,3-dioxygenase [IDO] and tryptophan [trp]. Although the essential amino acid trp can be metabolised via different pathways, a major route is the kynurenine pathway; IDO is the first enzyme of the pathway and is strongly stimulated by inflammatory molecules, particularly within the innate immune system. Various immunohistochemistry studies have demonstrated that the density of IDO-immuno-positive cells is significantly higher in both human brain with Alzheimer's disease [AD] and AD mice brain, suggesting that IDO-mediated activation of trp catabolism may be involved in amyloid aggregation and in neurofibrillary tangle formation. Accordingly, we sought to design trp analogues as possible anti-protein misfolding agents. We designed analogues of trp as putative IDO inhibitors. This was achieved by two approaches: a) designing analogues of trp by replacing functional groups with trp using bioisosteric replacements (e.g. tetrazole replacing carboxylate); or b) molecular modelling of the IDO enzyme active site. Compounds were synthesized, purified and evaluated in a battery of in vitro assays. Thirty five monocyclic heteroaromatic analogues of trp were synthesized (different from bi-aromatic analogues previously prepared by us). Eight of these analogues demonstrate micromolar/sub-micromolar efficacy in the following in vitro assays: [i] inhibiting Aβ-mediated increase in IL-1β, IL-4, IL-6, and/or TNFα cytokine release from neural tissue; [ii] inhibiting Abeta and tau aggregation (thioflavin-T Abeta aggregation fluorescence assay, thioflavin-S tau aggregation fluorescence assay, [iii] preventing Abeta conformational change to beta-sheet in circular dichroism, [iv] blocking Abeta misfolding in electron microscopy Abeta aggregation and Abeta42 biotinylated oligomerization assays; [v] able to cross the blood-brain barrier in both in vitro and in vivo models (MDR1-MDCK, mouse brain exposure PK with brain/plasma B/P >1). Two compounds demonstrated in vivo efficacy (radial arm water maze, Morris water maze) in APP/PS1 doubly transgenic amyloid mouse model of AD. IDO is a druggable target for the identification of new chemical entities as putative therapeutics for AD. Analogues of trp designed to inhibit IDO have in vitro and in vivo efficacy in the prevention of Abeta and tau misfolding.
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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) | 0.001 | 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".