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1.
Drugs ; 82(4): 455-460, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1700591

ABSTRACT

Molnupiravir (Lagevrio®) is an orally-administered antiviral prodrug that inhibits replication of RNA viruses through viral error induction. It is being developed by Merck and Ridgeback Biotherapeutics for the prevention and treatment of Coronavirus disease 2019 (COVID-19). Molnupiravir received its first approval on 4 November 2021 in the UK for the treatment of mild to moderate COVID-19 in adults with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic test and who have at least one risk factor for developing severe illness. Molnupiravir is filed for approval and has emergency use authorization for the treatment of COVID-19 in several countries, including the USA, Japan and those in the EU. This article summarizes the milestones in the development of molnupiravir leading to this first approval for COVID-19.


Subject(s)
COVID-19 , Adult , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Humans , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , SARS-CoV-2
3.
Nature ; 601(7894): 496, 2022 01.
Article in English | MEDLINE | ID: covidwho-1641925

Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Drug Development/trends , Drug Resistance, Viral , Research Personnel , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/supply & distribution , COVID-19/mortality , COVID-19/prevention & control , COVID-19 Vaccines/supply & distribution , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Drug Approval , Drug Combinations , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Hospitalization/statistics & numerical data , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Lactams/administration & dosage , Lactams/pharmacology , Lactams/therapeutic use , Leucine/administration & dosage , Leucine/pharmacology , Leucine/therapeutic use , Medication Adherence , Molecular Targeted Therapy , Mutagenesis , Nitriles/administration & dosage , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/administration & dosage , Proline/pharmacology , Proline/therapeutic use , Public-Private Sector Partnerships/economics , Ritonavir/administration & dosage , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/enzymology , SARS-CoV-2/genetics
5.
Biomed Pharmacother ; 146: 112517, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1561313

ABSTRACT

Rapid changes in the viral genome allow viruses to evade threats posed by the host immune response or antiviral drugs, and can lead to viral persistence in the host cells. RNA-dependent RNA polymerase (RdRp) is an essential enzyme in RNA viruses, which is involved in RNA synthesis through the formation of phosphodiester bonds. Therefore, in RNA viral infections such as SARS-CoV-2, RdRp could be a crucial therapeutic target. The present review discusses the promising application of RdRp inhibitors, previously approved or currently being tested in human clinical trials, in the treatment of RNA virus infections. Nucleoside inhibitors (NIs) bind to the active site of RdRp, while nonnucleoside inhibitors (NNIs) bind to allosteric sites. Given the absence of highly effective drugs for the treatment of COVID-19, the discovery of an efficient treatment for this pandemic is an urgent concern for researchers around the world. We review the evidence for molnupiravir (MK-4482, EIDD-2801), an antiviral drug originally designed for Alphavirus infections, as a potential preventive and therapeutic agent for the management of COVID-19. At the beginning of this pandemic, molnupiravir was in preclinical development for seasonal influenza. When COVID-19 spread dramatically, the timeline for development was accelerated to focus on the treatment of this pandemic. Real time consultation with regulators took place to expedite this program. We summarize the therapeutic potential of RdRp inhibitors, and highlight molnupiravir as a new small molecule drug for COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/enzymology , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Clinical Trials as Topic/methods , Cytidine/pharmacology , Cytidine/therapeutic use , Humans , Hydroxylamines/pharmacology , RNA-Dependent RNA Polymerase/metabolism
6.
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
7.
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
8.
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
10.
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
11.
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
12.
EBioMedicine ; 68: 103390, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1267655

ABSTRACT

BACKGROUND: Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach. METHOD: Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions. FINDINGS: The 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity. INTERPRETATION: The ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs. FUNDING: This work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S. C, CCHI: Cooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. ONE SENTENCE SUMMARY: The host immune response in COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/administration & dosage , COVID-19/genetics , Gene Expression Profiling/methods , Interleukin-15/genetics , Receptors, Interleukin-15/genetics , Virus Diseases/genetics , Animals , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/pharmacology , Antiviral Agents/pharmacology , Artificial Intelligence , Autopsy , COVID-19/drug therapy , COVID-19/immunology , Cricetinae , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Databases, Genetic , Disease Models, Animal , Gene Regulatory Networks/drug effects , Genetic Markers/drug effects , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Interleukin-15/blood , Lung/immunology , Mesocricetus , Pandemics , Receptors, Interleukin-15/blood , Virus Diseases/immunology
13.
J Biol Chem ; 297(1): 100867, 2021 07.
Article in English | MEDLINE | ID: covidwho-1265746

ABSTRACT

Molnupiravir, a prodrug of the nucleoside derivative ß-D-N4-hydroxycytidine (NHC), is currently in clinical trials for COVID-19 therapy. However, the biochemical mechanisms involved in molnupiravir-induced mutagenesis had not been explored. In a recent study, Gordon et al. demonstrated that NHC can be incorporated into viral RNA and subsequently extended and used as template for RNA-dependent RNA synthesis, proposing a mutagenesis model consistent with available virological evidence. Their study uncovers molecular mechanisms by which molnupiravir drives SARS-CoV-2 into error catastrophe.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/virology , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Cytidine/pharmacology , Humans , Point Mutation/drug effects , RNA, Viral/genetics , SARS-CoV-2/metabolism
14.
Nat Commun ; 12(1): 3309, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1260940

ABSTRACT

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , Pandemics , SARS-CoV-2 , Animals , COVID-19/prevention & control , COVID-19/virology , Cell Line , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Databases, Pharmaceutical , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , HeLa Cells , High-Throughput Screening Assays/methods , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Mesocricetus , Nelfinavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects
15.
J Biol Chem ; 297(1): 100770, 2021 07.
Article in English | MEDLINE | ID: covidwho-1225273

ABSTRACT

The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue ß-D-N4-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects; however, biochemical data of molnupiravir-induced mutagenesis have not been reported. Here we studied the effects of the active compound NHC 5'-triphosphate (NHC-TP) against the purified severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase complex. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12,841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate in the RNA primer strand. When embedded in the template strand, NHC-monophosphate supported the formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/virology , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , RNA, Viral/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Cytidine/pharmacology , Humans , Mutagenesis , Point Mutation/drug effects , SARS-CoV-2/metabolism
16.
Expert Opin Ther Pat ; 31(4): 325-337, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1039698

ABSTRACT

Introduction: The current SARS-CoV-2 pandemic urgently demands for both prevention and treatment strategies. RNA-dependent RNA-polymerase (RdRp), which has no counterpart in human cells, is an excellent target for drug development. Given the time-consuming process of drug development, repurposing drugs approved for other indications or at least successfully tested in terms of safety and tolerability, is an attractive strategy to rapidly provide an effective medication for severe COVID-19 cases.Areas covered: The currently available data and upcominSg studies on RdRp which can be repurposed to halt SARS-CoV-2 replication, are reviewed.Expert opinion: Drug repurposing and design of novel compounds are proceeding in parallel to provide a quick response and new specific drugs, respectively. Notably, the proofreading SARS-CoV-2 exonuclease activity could limit the potential for drugs designed as immediate chain terminators and favor the development of compounds acting through delayed termination. While vaccination is awaited to curb the SARS-CoV-2 epidemic, even partially effective drugs from repurposing strategies can be of help to treat severe cases of disease. Considering the high conservation of RdRp among coronaviruses, an improved knowledge of its activity in vitro can provide useful information for drug development or drug repurposing to combat SARS-CoV-2 as well as future pandemics.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Amides/pharmacology , Cytidine/analogs & derivatives , Cytidine/pharmacology , Drug Development , Drug Repositioning , Humans , Hydroxylamines/pharmacology , Pyrazines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/enzymology
17.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-960321

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
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