Structure‐function relationships in coronavirus and norovirus polymerases explored through the structure and activity of chimeric enzymes
Bibliographic record
Abstract
The COVID‐19 pandemic caused by the severe acute respiratory syndrome coronavirus‐2 (SARS CoV‐2) has spurred an unprecedented response from the scientific community to contribute timely solutions to help manage an urgent public health emergency. The RNA‐dependent RNA polymerase (RdRP) plays a critical function in replicating the genome of all RNA viruses and is one of the most intensively studied viral enzyme targets for the development of direct‐acting antiviral therapeutics. Comparisons of recently determined cryo‐EM structures of the SARS CoV‐2 RdRP with crystal structures of calicivirus, picornavirus and flavivirus RdRP's in complex with RNA and nucleoside analogue inhibitors suggest how differences in the sequences and structures of these RdRPs may result in differences in the activity of the enzyme as well as its sensitivity to different inhibitors. Molecular modeling, crystallographic studies and in vitro primer extension assays reveal how chimeric RdRPs bearing different sequence features from the RdRPs of SARS CoV‐2 and human norovirus GII.4 may contribute to differences in polymerase activity and the effects of nucleoside analogue inhibitors. These results suggest how some of the structural features of viral RdRPs may be productively targeted for the design of novel and more potent inhibitors to serve as lead compounds for the development of more effective antiviral therapeutics in the future.
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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 | 0.001 |
| 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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".