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2.
Med Sci Monit ; 28: e935952, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1596813

ABSTRACT

On 4th November 2021, the first oral antiviral drug for COVID-19, molnupiravir (Lagevrio®), received full regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. Molnupiravir is an orally bioavailable antiviral drug for use at home when a SARS-CoV-2 test is positive. On 22nd December 2022, the FDA granted emergency use authorization (EUA) for the oral antiviral drug, nirmatrelvir/ritonavir (Paxlovid®) for adults and children with mild and moderate COVID-19 at increased risk of progression to severe COVID-19. These regulatory drug approvals come at a crucial time when new variants of concern of the SARS-CoV-2 virus are spreading rapidly. Although the FDA approved remdesivir (Veklury®) on 22nd October 2020 for use in adults and children for the treatment of COVID-19 requiring hospitalization, its use has been limited by the requirement for intravenous administration in a healthcare facility. The four FDA-approved therapeutic neutralizing monoclonal antibodies, imdevimab, bamlanivimab, etesevimab, and casirivimab are costly and also require medically-supervised intravenous administration. The availability of effective, low-cost oral antiviral drugs available in a community setting that can be used at an early stage of SARS-CoV-2 infection is now a priority in controlling COVID-19. An increasing number of repurposed antiviral drugs are currently under investigation or in the early stages of regulatory approval. This Editorial aims to present an update on the current status of orally bioavailable antiviral drug treatments for SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Administration, Oral , Antibodies, Monoclonal/therapeutic use , Cytidine/therapeutic use , Drug Approval , Drug Repositioning/trends , Humans , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , United States , United States Food and Drug Administration
3.
Pharmacol Res Perspect ; 10(1): e00909, 2022 02.
Article in English | MEDLINE | ID: covidwho-1588891

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in china and has rapidly spread to many countries around the world. The effective pharmacotherapy can reduce the mortality of COVID-19. Antiviral medications are the candidate therapies for the management of COVID-19. Molnupiravir is an antiviral drug with anti-RNA polymerase activity and currently is under investigation for the treatment of patients with COVID-19. This review focuses on summarizing published literature for the mechanism of action, safety, efficacy, and clinical trials of molnupiravir in the treatment of COVID-19 patients.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , COVID-19/virology , Clinical Trials as Topic , Cytidine/therapeutic use , Drug Interactions , Humans , SARS-CoV-2/isolation & purification
5.
J Infect Dis ; 224(3): 415-419, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1526165

ABSTRACT

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. ß-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.


Subject(s)
Antiviral Agents/pharmacology , Cytidine/analogs & derivatives , Mutagens/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/adverse effects , CHO Cells/drug effects , Cells, Cultured , Cricetulus , Cytidine/adverse effects , Cytidine/pharmacology , Dose-Response Relationship, Drug , Mutagenesis/drug effects , Mutagens/adverse effects , SARS-CoV-2/genetics , Virus Replication/drug effects
10.
Virology ; 564: 33-38, 2021 12.
Article in English | MEDLINE | ID: covidwho-1447220

ABSTRACT

Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight that the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.


Subject(s)
Coronavirus 229E, Human/genetics , Coronavirus Infections/drug therapy , Coronavirus NL63, Human/genetics , Coronavirus OC43, Human/genetics , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Common Cold/drug therapy , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/physiology , Coronavirus NL63, Human/drug effects , Coronavirus NL63, Human/physiology , Coronavirus OC43, Human/drug effects , Coronavirus OC43, Human/physiology , Cytidine/pharmacology , Humans , Molecular Docking Simulation , Protein Binding/drug effects , Pyrrolidines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Seasons , Sulfonic Acids/pharmacology , Virus Replication/drug effects , Virus Replication/genetics
11.
Molecules ; 26(19)2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1438674

ABSTRACT

The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase 3 clinical trial against COVID-19. The objective of this review article is to enlighten the researchers working on COVID-19 about the discovery, recent developments, and patents related to molnupiravir. Molnupiravir was originally developed for the treatment of influenza at Emory University, USA. However, this drug has also demonstrated activity against a variety of viruses, including SARS-CoV-2. Now it is being jointly developed by Emory University, Ridgeback Biotherapeutics, and Merck to treat COVID-19. The published clinical data indicate a good safety profile, tolerability, and oral bioavailability of molnupiravir in humans. The patient-compliant oral dosage form of molnupiravir may hit the market in the first or second quarter of 2022. The patent data of molnupiravir revealed its granted compound patent and process-related patent applications. We also anticipate patent filing related to oral dosage forms, inhalers, and a combination of molnupiravir with marketed drugs like remdesivir, favipiravir, and baricitinib. The current pandemic demands a patient compliant, safe, tolerable, and orally effective COVID-19 treatment. The authors believe that molnupiravir meets these requirements and is a breakthrough COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Drug Discovery , Hydroxylamines/therapeutic use , SARS-CoV-2/drug effects , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Clinical Trials as Topic , Cytidine/administration & dosage , Cytidine/chemistry , Cytidine/therapeutic use , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/chemistry , Patents as Topic , RNA-Directed DNA Polymerase/metabolism , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/therapeutic use , SARS-CoV-2/enzymology , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolism
12.
EBioMedicine ; 72: 103595, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1433162

ABSTRACT

BACKGROUND: Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients. METHODS: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds. FINDINGS: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. INTERPRETATION: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19. FUNDING: stated in the acknowledgment.


Subject(s)
Amides/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Lung/virology , Pyrazines/therapeutic use , Amides/pharmacology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/transmission , Cytidine/pharmacology , Cytidine/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Female , Hydroxylamines/pharmacology , Mesocricetus , Pyrazines/pharmacology , RNA, Viral , Treatment Outcome , Viral Load
13.
J Infect Dis ; 224(5): 749-753, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1411568

ABSTRACT

The emergence of SARS-CoV-2 variants of concern (VoCs) has exacerbated the COVID-19 pandemic. Currently available monoclonal antibodies and vaccines appear to have reduced efficacy against some of these VoCs. Antivirals targeting conserved proteins of SARS-CoV-2 are unlikely to be affected by mutations arising in VoCs and should therefore be effective against emerging variants. We here investigate the efficacy of molnupiravir, currently in phase 2 clinical trials, in hamsters infected with Wuhan strain or B.1.1.7 and B.1.351 variants. Molnupiravir proved to be effective against infections with each of the variants and therefore may have potential combating current and future emerging VoCs.


Subject(s)
COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/virology , Cricetinae , Cytidine/pharmacology , Disease Models, Animal , Female , Humans , Mutation/drug effects , Pandemics/prevention & control , SARS-CoV-2/immunology
15.
Mol Pharmacol ; 100(6): 548-557, 2021 12.
Article in English | MEDLINE | ID: covidwho-1403004

ABSTRACT

Equilibrative nucleoside transporters (ENTs) are present at the blood-testis barrier (BTB), where they can facilitate antiviral drug disposition to eliminate a sanctuary site for viruses detectable in semen. The purpose of this study was to investigate ENT-drug interactions with three nucleoside analogs, remdesivir, molnupiravir, and molnupiravir's active metabolite, ß-d-N4-hydroxycytidine (EIDD-1931), and four non-nucleoside molecules repurposed as antivirals for coronavirus disease 2019 (COVID-19). The study used three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors and Bayesian machine learning models to identify potential interactions with these transporters. In vitro transport experiments demonstrated that remdesivir was the most potent inhibitor of ENT-mediated [3H]uridine uptake (ENT1 IC50: 39 µM; ENT2 IC50: 77 µM), followed by EIDD-1931 (ENT1 IC50: 259 µM; ENT2 IC50: 467 µM), whereas molnupiravir was a modest inhibitor (ENT1 IC50: 701 µM; ENT2 IC50: 851 µM). Other proposed antivirals failed to inhibit ENT-mediated [3H]uridine uptake below 1 mM. Remdesivir accumulation decreased in the presence of 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR) by 30% in ENT1 cells (P = 0.0248) and 27% in ENT2 cells (P = 0.0054). EIDD-1931 accumulation decreased in the presence of NBMPR by 77% in ENT1 cells (P = 0.0463) and by 64% in ENT2 cells (P = 0.0132), which supported computational predictions that both are ENT substrates that may be important for efficacy against COVID-19. NBMPR failed to decrease molnupiravir uptake, suggesting that ENT interaction is likely inhibitory. Our combined computational and in vitro data can be used to identify additional ENT-drug interactions to improve our understanding of drugs that can circumvent the BTB. SIGNIFICANCE STATEMENT: This study identified remdesivir and EIDD-1931 as substrates of equilibrative nucleoside transporters 1 and 2. This provides a potential mechanism for uptake of these drugs into cells and may be important for antiviral potential in the testes and other tissues expressing these transporters.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/metabolism , Cytidine/analogs & derivatives , Equilibrative Nucleoside Transporter 1/metabolism , Equilibrative-Nucleoside Transporter 2/metabolism , SARS-CoV-2/metabolism , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/metabolism , Alanine/administration & dosage , Alanine/metabolism , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/metabolism , Cytidine/administration & dosage , Cytidine/metabolism , Dose-Response Relationship, Drug , Drug Interactions/physiology , HeLa Cells , Humans , Protein Binding/drug effects , Protein Binding/physiology , SARS-CoV-2/drug effects
16.
J Pharm Biomed Anal ; 206: 114356, 2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1386097

ABSTRACT

In light of the recent global pandemic, Molnupiravir (MPV) or EIDD-2801, developed for the treatment of patients with uncomplicated influenza, is now being trialled for the treatment of infections caused by highly pathogenic coronaviruses, including COVID-19. A sensitive LC-MS/MS method was developed and validated for the simultaneous quantification of MPV and its metabolite ß-d-N4-hydroxycytidine (NHC) in human plasma and saliva. The analytes were extracted from the matrices by protein precipitation using acetonitrile. This was followed by drying and subsequently injecting the reconstituted solutions onto the column. Chromatographic separation was achieved using a polar Atlantis C18 column with gradient elution of 1 mM Ammonium acetate in water (pH4.3) and 1 mM Ammonium acetate in acetonitrile. Analyte detection was conducted in negative ionisation mode using SRM. Analysis was performed using stable isotopically labelled (SIL) internal standards (IS). The m/z transitions were: MPV (328.1→126.0), NHC (258.0→125.9) and MPV-SIL (331.0→129.0), NHC-SIL (260.9→128.9). Validation was over a linear range of 2.5-5000 ng/ml for both plasma and saliva. Across four different concentrations, precision and accuracy (intra- and inter-day) were 15%; and recovery of both analytes from plasma and saliva was between 95% and 100% and 65-86% respectively. Clinical pharmacokinetic studies are underway utilising this method for determination of MPV and its metabolite in patients with COVID-19 infection.


Subject(s)
COVID-19 , Saliva , Chromatography, Liquid , Cytidine/analogs & derivatives , Humans , Hydroxylamines , Reproducibility of Results , SARS-CoV-2 , Tandem Mass Spectrometry
17.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1182: 122921, 2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1385835

ABSTRACT

The novel antiviral prodrug molnupiravir is under evaluation for the treatment of SARS-CoV-2. Molnupiravir is converted to ß-D-N4-hydroxycytidine (NHC), which is the primary form found in systemic circulation. ß-D-N4-hydroxycytidine-triphosphate (NHCtp) is the bioactive anabolite produced intracellularly. Sensitive and accurate bioanalytical methods are required to characterize NHC and NHCtp pharmacokinetics in clinical trials. Human K2EDTA plasma or peripheral blood mononuclear cell (PBMC) lysates were spiked with NHC (plasma) or NHCtp (PBMC), respectively. Following the addition of isotopically-labeled internal standards and sample extraction via protein precipitation or lysate dilution, respectively, samples were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. Methods were validated in accordance with FDA Bioanalytical Method Validation recommendations. NHC can be quantified in plasma with a lower limit of quantification (LLOQ) of 1 ng/mL; the primary linearity of the assay is 1-5000 ng/mL. Assay precision and accuracy were ≤ 6.40% and ≤ ± 6.37%, respectively. NHC is unstable in whole blood and has limited stability in plasma at room temperature. The calibration range for NHCtp in PBMC lysates is 1-1500 pmol/sample, and the assay has an LLOQ of 1 pmol/sample. Assay precision and accuracy were ≤ 11.8% and ≤± 11.2%. Ion suppression was observed for both analytes; isotopically-labeled internal standards showed comparable ion suppression, resulting in negligible (<5%) relative matrix effects. Sensitive, specific, and dynamic LC-MS/MS assays have been developed and validated for the quantification of NHC in plasma and NHCtp in PBMC lysates. The described methods are appropriate for use in clinical trials.


Subject(s)
Cytidine/analogs & derivatives , Cytidine/blood , Cytidine/chemistry , Humans , Reproducibility of Results
18.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-1387364

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/transmission , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/immunology , Chlorocebus aethiops , Cytidine/pharmacology , Cytokines/immunology , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Female , Ferrets , Random Allocation , Vero Cells
19.
Trials ; 22(1): 561, 2021 Aug 23.
Article in English | MEDLINE | ID: covidwho-1370945

ABSTRACT

A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 , Cytidine/therapeutic use , Hydroxylamines/therapeutic use , Ribonucleosides , Cytidine/analogs & derivatives , Humans , United States
20.
Nat Struct Mol Biol ; 28(9): 740-746, 2021 09.
Article in English | MEDLINE | ID: covidwho-1354110

ABSTRACT

Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp-RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.


Subject(s)
COVID-19/prevention & control , Cytidine/analogs & derivatives , Hydroxylamines/metabolism , Mutagenesis/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Base Sequence , COVID-19/drug therapy , COVID-19/virology , Cytidine/chemistry , Cytidine/metabolism , Cytidine/pharmacology , Humans , Hydroxylamines/chemistry , Hydroxylamines/pharmacology , Models, Molecular , Molecular Structure , Mutagenesis/drug effects , Mutation/drug effects , Mutation/genetics , Nucleic Acid Conformation , Protein Binding/drug effects , Protein Conformation , RNA, Viral/chemistry , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects , Virus Replication/genetics
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