A naturally occurring <scp>G11S</scp> mutation in the <scp>3C</scp>‐like protease from the <scp>SARS‐CoV</scp>‐2 virus dramatically weakens the dimer interface
Bibliographic record
Abstract
Abstract The 3C‐like protease (3CL pro ) is crucial to the replication of SARS‐CoV‐2, the causative agent of COVID‐19, and is the target of several successful drugs including Paxlovid and Xocova. Nevertheless, the emergence of viral resistance underlines the need for alternative drug strategies. 3CL pro only functions as a homodimer, making the protein–protein interface an attractive drug target. Dimerization is partly mediated by a conserved glycine at position 11. However, some naturally occurring SARS‐CoV‐2 sequences contain a serine at this position, potentially disrupting the dimer. We have used concentration‐dependent activity assays and mass spectrometry to show that indeed the G11S mutation reduces the stability of the dimer by 600‐fold. This helps to set a quantitative benchmark for the minimum potency required of any future protein–protein interaction inhibitors targeting 3CL pro and raises interesting questions regarding how coronaviruses bearing such weakly dimerizing 3CL pro enzymes are capable of replication.
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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 | 0.010 | 0.018 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.007 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.009 | 0.003 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 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".