p-Alkoxy Substituted Anisomycins with Potent Anti-Trypanosomiasis Activityand Expanded Modes of Action
Bibliographic record
Abstract
Neglected tropical diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi present a major public healthcare issue due in part to emerging resistance. Exploring multiple targeting ligands, conjugates composed of analogs from the ribosomal inhibitor anisomycin and glycosomal inhibitory almiramide peptides were made and shown to be inactive compared to the parent components. On the other hand, attachment of walkynyl chains characteristic of the lipid tails of anti-parasitic peptides to the p-position of anisomycin, gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant Leishmania strains. Cryo-electron microscopy revealed that the O-propargyl anisomycin analog bound similarly to the highly conserved peptidyl transferase center of the ribosome as the parent inhibitor. Thermal proteomic profiling and gene ontology analysis demonstrated that O-propargyl anisomycin exhibited a broader mode of action including activity against glycosome-associated proteins. Structure-activity study has revealed the utility of alkynyl substituents for improving antiparasitic activity against resistant strains by enlarging mode of action paving the way towards novel therapy against trypanosomatid infections.
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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) | 0.002 | 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".