Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine 1, a first-in-class inhibitor of the CHIKV nsP2 RNA helicase (nsP2hel), into its constitutive enantiomers and characterization of their antiviral activity. The enantiomer ( R )- 1 exhibited potent inhibition of viral replication, nsP2hel ATPase activity, and dsRNA unwinding, while the ( S )- 1 enantiomer was >100-fold less active. The ( R )- 1 enantiomer also demonstrated a high selectivity for CHIKV over other RNA viruses and for nsP2hel over other RNA helicases. Direct binding of ( R )- 1 to the nsP2hel protein was confirmed by 19 F NMR. Biophysical and structural studies revealed conformational polymorphism in the spirocyclic scaffold of ( R )- 1, suggesting a potential role of thermal mobility of the ligand in allosteric inhibition of nsP2hel. Collectively, these findings designate ( R )- 1 (RA-NSP2- 1 ) as a high-quality chemical probe and ( S )- 1 (RA-NSP2- 1 N) as a negative control for probing the biology of alphavirus RNA helicases.
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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 | 0.000 |
| 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 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".