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2.
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
3.
Nature ; 592(7853): 277-282, 2021 04.
Article in English | MEDLINE | ID: covidwho-1387425

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , COVID-19/virology , Evolution, Molecular , Mutagenesis/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Chronic Disease , Genome, Viral/drug effects , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing , Humans , Immune Evasion/drug effects , Immune Evasion/genetics , Immune Evasion/immunology , Immune Tolerance/drug effects , Immune Tolerance/immunology , Immunization, Passive , Male , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/immunology , Mutation , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Viral Load/drug effects , Virus Shedding
4.
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
5.
J Infect Dis ; 224(3): 415-419, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1221478

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
6.
Drug Res (Stuttg) ; 71(3): 166-170, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-919370

ABSTRACT

A recent outbreak of coronavirus disease 2019 (COVID-19) caused by the novel coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan, China, at the end of 2019 and then spread rapidly all over the world. However, there are no specific antiviral therapies for COVID-19, using the agents which approved or in development for other viral infections is one of the potentially quickest ways to find treatment for this new viral infection. Favipiravir is an effective agent that acts as a nucleotide analog that selectively inhibits the viral RNA dependent RNA polymerase or causes lethal mutagenesis upon incorporation into the virus RNA. In view of recent studies and discussion on favipiravir, in this mini review we aimed to summarize the clinical trials studying the efficacy and safety of favipiravir in patients with COVID-19.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Pyrazines/therapeutic use , SARS-CoV-2/drug effects , Amides/pharmacology , Antiviral Agents/pharmacology , COVID-19/virology , Clinical Trials as Topic , Humans , Mutagenesis/drug effects , Pyrazines/pharmacology , RNA, Viral/drug effects , RNA, Viral/genetics , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Treatment Outcome
7.
J Transl Med ; 18(1): 390, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-863645

ABSTRACT

While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral from the ground up is time intensive. Therefore, most antiviral discovery efforts are focused on the re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing, there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and therefore rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular proteins that are hijacked by viruses can potentially offer broad-spectrum targets for the development of future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the development and selection of drug resistant mutations. Given that most approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.


Subject(s)
Antiviral Agents , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Discovery , Health Services Needs and Demand , Host-Pathogen Interactions/drug effects , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/classification , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Delivery Systems/methods , Drug Delivery Systems/standards , Drug Discovery/organization & administration , Drug Discovery/standards , Drug Discovery/trends , Global Health , Health Services Needs and Demand/organization & administration , Health Services Needs and Demand/standards , Health Services Needs and Demand/trends , Humans , Mutagenesis/drug effects , Needs Assessment/organization & administration , Needs Assessment/standards , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Virus Internalization/drug effects
8.
Nat Commun ; 11(1): 4682, 2020 09 17.
Article in English | MEDLINE | ID: covidwho-779999

ABSTRACT

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.


Subject(s)
Amides/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/genetics , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Pyrazines/pharmacology , Amides/pharmacokinetics , Animals , Antiviral Agents/pharmacokinetics , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/virology , Coronavirus RNA-Dependent RNA Polymerase , Models, Molecular , Mutagenesis/drug effects , Pandemics , Pneumonia, Viral/virology , Pyrazines/pharmacokinetics , RNA, Viral/genetics , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2 , Sequence Analysis , Vero Cells , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
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