Commentary Potential Enhancement by 3-Deazauridine of the Antiviral Activity of Molnupiravir in Patients with COVID-19
Bibliographic record
Abstract
Background: Molnupiravir, N4-hydroxycytidine-5’-isopropyl ester, is an oral prodrug of N4-deoxycytidine (NHC), a nucleoside analog, which has in vitro activity against SARS-CoV-2. NHC is phosphorylated in cells to NHC triphosphate (NHC-TP), which is incorporated into viral RNA, leading to epigenetic catastrophe of the viral genome and inhibition of viral replication. The antiviral activity against SARS-CoV-2 is dependent on the number of molecules of NHC-TP incorporated into viral RNA. Clinical studies in patients with COVID-19 showed that treatment with molnupiravir for 5 days decreases the risk of hospitalization and death as compared with placebo. Objective: It should be possible to enhance the antiviral activity of NHC-TP against SARS-CoV-2 by the use of the biochemical modulator, 3-deazauridine (3DU). 3DU is an inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in the intracellular pool size of CTP. Since NHC-TP competes with CTP for incorporation into viral RNA in the reaction catalyzed by the SARS-CoV-2 viral RNA-dependent RNA polymerase, the reduction in the level of CTP should result in a significant enhancement of the incorporation of NHC-TP into viral RNA and an enhancement of its antiviral activity. Methods: Analysis of the publications of 3DU and cytosine nucleoside analogues support the hypothesis that 3DU enhances the pharmacological action of the analogues. Results: 3-DU increased the incorporation of 5-azacytidine into RNA and 5-aza-deoxycytidine into DNA of leukemic cells with an enhancement of their antineoplastic action. 3-DU potentiated the antiviral activity against HIV-1 activity by the cytosine nucleoside analogues: 2’-deoxy-3’-thiacytidine (3TC; lamivudine) and 2’,3’-dideoxycytidine (ddC). This anti-HIV-1 activity of 3DU was associated with a reduction in the intracellular pool size of dCTP and increased incorporation of triphosphates of 3TC and ddC into DNA by the HIV-1 reverse transcriptase. The reduction of CTP levels in cells by 3-DU also leads to a reduction in dCTP since CTP is its precursor. Conclusion: The preclinical studies on 3-DU indicate that it can enhance the pharmacological activity of both ribo- and deoxyribonucleoside analogues against neoplastic cells and viral infected cells. These observations suggest that 3-DU also has the potential to enhance the antiviral activity of molnupiravir and arrest the progression of the disease in patients with COVID-19.
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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 | 0.004 |
| 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".