Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5′-Monophosphate
Why this work is in the frame
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Bibliographic record
Abstract
Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39) catalyzes the extracellular hydrolysis of ATP generating AMP, while ecto-5'-nucleotidase (CD73) further hydrolyzes AMP yielding immunosuppressive adenosine. 8-Butylthioadenosine 5'-monophosphate (8-BuS-AMP) was described as a CD39 inhibitor but has been poorly characterized. The standard CD39 antagonist ARL 67156 is not suitable for in vivo studies due to metabolic instability. In the present study, we optimized and upscaled the synthesis of 8-BuS-AMP and performed a comprehensive investigation of its properties. It behaves as a competitive inhibitor at human and mouse CD39, and additionally inhibits CD73. Docking studies using a homology model of human CD39 and determination of an atomic-resolution (1.06 Å) cocrystal structure with human CD73 indicated the inhibitor's interactions within the substrate binding pockets and explained the compound's stability toward hydrolysis. 8-BuS-AMP is metabolically highly stable in human and mouse liver microsomes. It inhibited ε-adenosine formation from ε-ATP and ε-AMP in human synovial fluid and enhanced activation and proliferation of peripheral human T lymphocytes. Thus, 8-BuS-AMP is a recommended tool compound for studying purinergic signaling in vitro and in vivo, being superior to the standard CD39 inhibitor ARL 67156. Moreover, it may serve as a lead structure to develop drugs for the immunotherapy of cancer.
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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 it