Identification of Phialomustin-B (PHL-B) as a Novel Natural TRPA1 Channel Inhibitor
Bibliographic record
Abstract
The TRPA1 channel has recently emerged as a critical target for pain relief since its antagonists target the beginning of the pain transduction pathway and, thus, are devoid of side effects such as sedation, dizziness, somnolence, or cognitive impairment. Despite this clinical significance, currently, no TRPA1 inhibitors suitable for therapeutic usage exist to target these channels. Since ancient times, natural products have been known to be a rich source of new drugs, useful therapeutic agents, as well as pharmacological tools. To discover novel natural TRPA1 antagonists, we screened a diverse range of natural products belonging to medicinal plants and endophytic microbes. Using a fluorescence-based calcium-influx assay, we identified that an unsaturated fatty acid known as Phialomustin B (PHL-B) exhibited potent TRPA1 inhibitory activity (IC50 = 1.35 ± 0.3 μM). In subsequent whole-cell/cell-attached patch clamp recordings, PHL-B displayed a reversible and voltage-dependent block of the TRPA1 ion channel at submicromolar concentrations. Our off-target profiling data indicated that PHL-B selectively inhibited TRPA1 channels without any considerable effect on other thermo-TRPs such as TRPV1, TRPV4, and TRPM8 channels. Docking of PHL-B on the TRPA1 channel structure revealed a binding pocket in a hotspot region for a gain-of-function mutation, N855S, that results in pain syndromes. Mutagenesis data demonstrated that I860 and K868 residues of the TRPA1 channel participate in PHL-B interactions, and when mutated, the potency of PHL-B is significantly mitigated. Collectively, our data indicate that PHL-B could function as a novel natural antinociceptive agent targeting TRPA1-related diseases with a TRPA1-mediated adverse component.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".