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1.
Nucleic Acids Res ; 50(3): 1484-1500, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1624985

ABSTRACT

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Exoribonucleases/metabolism , Genome, Viral/genetics , Genomic Instability , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/metabolism , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Exoribonucleases/antagonists & inhibitors , Genome, Viral/drug effects , Genomic Instability/drug effects , Genomic Instability/genetics , HIV Integrase Inhibitors/pharmacology , Isoindoles/pharmacology , Multienzyme Complexes/antagonists & inhibitors , Multienzyme Complexes/metabolism , Organoselenium Compounds/pharmacology , RNA, Viral/biosynthesis , RNA, Viral/genetics , Raltegravir Potassium/pharmacology , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Virus Replication/drug effects , Virus Replication/genetics
2.
Antiviral Res ; 197: 105232, 2022 01.
Article in English | MEDLINE | ID: covidwho-1588314

ABSTRACT

We report the in vitro antiviral activity of DZNep (3-Deazaneplanocin A; an inhibitor of S-adenosylmethionine-dependent methyltransferase) against SARS-CoV-2, besides demonstrating its protective efficacy against lethal infection of infectious bronchitis virus (IBV, a member of the Coronaviridae family). DZNep treatment resulted in reduced synthesis of SARS-CoV-2 RNA and proteins without affecting other steps of viral life cycle. We demonstrated that deposition of N6-methyl adenosine (m6A) in SARS-CoV-2 RNA in the infected cells recruits heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), an RNA binding protein which serves as a m6A reader. DZNep inhibited the recruitment of hnRNPA1 at m6A-modified SARS-CoV-2 RNA which eventually suppressed the synthesis of the viral genome. In addition, m6A-marked RNA and hnRNPA1 interaction was also shown to regulate early translation to replication switch of SARS-CoV-2 genome. Furthermore, abrogation of methylation by DZNep also resulted in defective synthesis of the 5' cap of viral RNA, thereby resulting in its failure to interact with eIF4E (a cap-binding protein), eventually leading to a decreased synthesis of viral proteins. Most importantly, DZNep-resistant mutants could not be observed upon long-term sequential passage of SARS-CoV-2 in cell culture. In summary, we report the novel role of methylation in the life cycle of SARS-CoV-2 and propose that targeting the methylome using DZNep could be of significant therapeutic value against SARS-CoV-2 infection.


Subject(s)
Adenosine/analogs & derivatives , Genome, Viral/drug effects , Methyltransferases/antagonists & inhibitors , SARS-CoV-2/drug effects , Adenosine/pharmacology , Animals , Chick Embryo , Chlorocebus aethiops , Chromatin Immunoprecipitation Sequencing , DNA Methylation/drug effects , DNA Methylation/physiology , Drug Resistance, Viral/drug effects , Genome, Viral/genetics , Heterogeneous Nuclear Ribonucleoprotein A1/metabolism , Humans , Lethal Dose 50 , Mice , Protein Biosynthesis/drug effects , RNA, Viral/drug effects , RNA, Viral/metabolism , Rabbits , SARS-CoV-2/genetics , Specific Pathogen-Free Organisms , Transcription, Genetic/drug effects , Vero Cells
3.
Viruses ; 13(11)2021 11 04.
Article in English | MEDLINE | ID: covidwho-1538544

ABSTRACT

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses' genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV's attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.


Subject(s)
Antiviral Agents/pharmacology , G-Quadruplexes , Herpesvirus 1, Suid/genetics , Replication Origin/genetics , Animals , Antiviral Agents/chemistry , Cell Line , DNA Replication/drug effects , DNA, Viral/biosynthesis , DNA, Viral/chemistry , DNA, Viral/drug effects , Fused-Ring Compounds/chemistry , Fused-Ring Compounds/pharmacology , G-Quadruplexes/drug effects , Genome, Viral/drug effects , Genome, Viral/genetics , Herpesvirus 1, Suid/drug effects , Herpesvirus 1, Suid/physiology , Replication Origin/drug effects , Swine , Virus Replication/drug effects
4.
Appl Environ Microbiol ; 87(24): e0182421, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1532953

ABSTRACT

As a result of the novel coronavirus disease 2019 pandemic, strengthening control measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an urgent global issue. In addition to antiviral therapy and vaccination strategies, applying available virucidal substances for SARS-CoV-2 inactivation is also a target of research to prevent the spread of infection. Here, we evaluated the SARS-CoV-2 inactivation activity of a copper iodide (CuI) nanoparticle dispersion, which provides Cu+ ions having high virucidal activity, and its mode of actions. In addition, the utility of CuI-doped film and fabric for SARS-CoV-2 inactivation was evaluated. The CuI dispersion exhibited time-dependent rapid virucidal activity. Analyses of the modes of action of CuI performed by Western blotting and real-time reverse transcription-PCR targeting viral proteins and the genome revealed that CuI treatment induced the destruction of these viral components. In this setting, the indirect action of CuI-derived reactive oxygen species contributed to the destruction of viral protein. Moreover, the CuI-doped film and fabric demonstrated rapid inactivation of the SARS-CoV-2 solution in which the viral titer was high. These findings indicated the utility of the CuI-doped film and fabric as anti-SARS-CoV-2 materials for the protection of high-touch environmental surfaces and surgical masks/protective clothes. Throughout this study, we demonstrated the effectiveness of CuI nanoparticles for inactivating SARS-CoV-2 and revealed a part of its virucidal mechanism of action. IMPORTANCE The COVID-19 pandemic has caused an unprecedented number of infections and deaths. As the spread of the disease is rapid and the risk of infection is severe, hand and environmental hygiene may contribute to suppressing contact transmission of SARS-CoV-2. Here, we evaluated the SARS-CoV-2 inactivation activity of CuI nanoparticles, which provide the Cu+ ion as an antiviral agent, and we provided advanced findings of the virucidal mechanisms of action of Cu+. Our results showed that the CuI dispersion, as well as CuI-doped film and fabric, rapidly inactivated SARS-CoV-2 with a high viral titer. We also demonstrated the CuI's virucidal mechanisms of action, specifically the destruction of viral proteins and the genome by CuI treatment. Protein destruction largely depended on CuI-derived reactive oxygen species. This study provides novel information about the utility and mechanisms of action of promising virucidal material against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , Copper/pharmacology , Disinfection/methods , Iodides/pharmacology , SARS-CoV-2/drug effects , Animals , COVID-19/transmission , Cell Line , Chlorocebus aethiops , Disinfectants/pharmacology , Genome, Viral/drug effects , Humans , Nanoparticles , Reactive Oxygen Species/metabolism , SARS-CoV-2/genetics , Vero Cells
6.
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
7.
Molecules ; 26(16)2021 Aug 08.
Article in English | MEDLINE | ID: covidwho-1348676

ABSTRACT

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is producing a large number of infections and deaths globally, the development of supportive and auxiliary treatments is attracting increasing attention. Here, we evaluated SARS-CoV-2-inactivation activity of the polyphenol-rich tea leaf extract TY-1 containing concentrated theaflavins and other virucidal catechins. The TY-1 was mixed with SARS-CoV-2 solution, and its virucidal activity was evaluated. To evaluate the inhibition activity of TY-1 in SARS-CoV-2 infection, TY-1 was co-added with SARS-CoV-2 into cell culture media. After 1 h of incubation, the cell culture medium was replaced, and the cells were further incubated in the absence of TY-1. The viral titers were then evaluated. To evaluate the impacts of TY-1 on viral proteins and genome, TY-1-treated SARS-CoV-2 structural proteins and viral RNA were analyzed using western blotting and real-time RT-PCR, respectively. TY-1 showed time- and concentration-dependent virucidal activity. TY-1 inhibited SARS-CoV-2 infection of cells. The results of western blotting and real-time RT-PCR suggested that TY-1 induced structural change in the S2 subunit of the S protein and viral genome destruction, respectively. Our findings provided basic insights in vitro into the possible value of TY-1 as a virucidal agent, which could enhance the current SARS-CoV-2 control measures.


Subject(s)
COVID-19/virology , Polyphenols/pharmacology , SARS-CoV-2/drug effects , Tea/chemistry , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Biflavonoids/chemistry , Biflavonoids/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Camellia sinensis/metabolism , Catechin/chemistry , Catechin/pharmacology , Cell Line , Chlorocebus aethiops , Genome, Viral/drug effects , Humans , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Polyphenols/isolation & purification , SARS-CoV-2/metabolism , Vero Cells , Viral Load/drug effects
8.
Angew Chem Int Ed Engl ; 60(33): 18144-18151, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1206743

ABSTRACT

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.


Subject(s)
5' Untranslated Regions , Antiviral Agents/pharmacology , Macromolecular Substances/pharmacology , RNA/metabolism , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Chlorocebus aethiops , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coordination Complexes/pharmacology , Genome, Viral/drug effects , Macromolecular Substances/chemistry , Macromolecular Substances/metabolism , Metals, Heavy/chemistry , Molecular Dynamics Simulation , RNA/genetics , SARS-CoV-2/chemistry , Vero Cells
9.
Viruses ; 13(2)2021 02 02.
Article in English | MEDLINE | ID: covidwho-1154509

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally. Although measures to control SARS-CoV-2, namely, vaccination, medication, and chemical disinfectants are being investigated, there is an increase in the demand for auxiliary antiviral approaches using natural compounds. Here we have focused on hydroxytyrosol (HT)-rich aqueous olive pulp extract (HIDROX®) and evaluated its SARS-CoV-2-inactivating activity in vitro. We showed that the HIDROX solution exhibits time- and concentration-dependent SARS-CoV-2-inactivating activities, and that HIDROX has more potent virucidal activity than pure HT. The evaluation of the mechanism of action suggested that both HIDROX and HT induced structural changes in SARS-CoV-2, which changed the molecular weight of the spike proteins. Even though the spike protein is highly glycosylated, this change was induced regardless of the glycosylation status. In addition, HIDROX or HT treatment disrupted the viral genome. Moreover, the HIDROX-containing cream applied on film showed time- and concentration-dependent SARS-CoV-2-inactivating activities. Thus, the HIDROX-containing cream can be applied topically as an antiviral hand cream. Our findings suggest that HIDROX contributes to improving SARS-CoV-2 control measures.


Subject(s)
Antiviral Agents/pharmacology , Olea , Phenylethyl Alcohol/analogs & derivatives , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Administration, Topical , Animals , Antiviral Agents/chemistry , Carbohydrates/chemistry , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins/chemistry , Genome, Viral/drug effects , Glycosylation , Microbial Sensitivity Tests , Phenylethyl Alcohol/administration & dosage , Phenylethyl Alcohol/pharmacology , Phosphoproteins/chemistry , Plant Extracts/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Skin Cream , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Inactivation/drug effects
10.
PLoS Pathog ; 17(3): e1009439, 2021 03.
Article in English | MEDLINE | ID: covidwho-1133695

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the global pandemic of COVID-19. SARS-CoV-2 is classified as a biosafety level-3 (BSL-3) agent, impeding the basic research into its biology and the development of effective antivirals. Here, we developed a biosafety level-2 (BSL-2) cell culture system for production of transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). This trVLP expresses a reporter gene (GFP) replacing viral nucleocapsid gene (N), which is required for viral genome packaging and virion assembly (SARS-CoV-2 GFP/ΔN trVLP). The complete viral life cycle can be achieved and exclusively confined in the cells ectopically expressing SARS-CoV or SARS-CoV-2 N proteins, but not MERS-CoV N. Genetic recombination of N supplied in trans into viral genome was not detected, as evidenced by sequence analysis after one-month serial passages in the N-expressing cells. Moreover, intein-mediated protein trans-splicing approach was utilized to split the viral N gene into two independent vectors, and the ligated viral N protein could function in trans to recapitulate entire viral life cycle, further securing the biosafety of this cell culture model. Based on this BSL-2 SARS-CoV-2 cell culture model, we developed a 96-well format high throughput screening for antivirals discovery. We identified salinomycin, tubeimoside I, monensin sodium, lycorine chloride and nigericin sodium as potent antivirals against SARS-CoV-2 infection. Collectively, we developed a convenient and efficient SARS-CoV-2 reverse genetics tool to dissect the virus life cycle under a BSL-2 condition. This powerful tool should accelerate our understanding of SARS-CoV-2 biology and its antiviral development.


Subject(s)
COVID-19/virology , Cell Culture Techniques/methods , SARS-CoV-2/physiology , Antiviral Agents/pharmacology , Containment of Biohazards , Genome, Viral/drug effects , High-Throughput Screening Assays , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , Virus Replication/drug effects
11.
Int J Biol Macromol ; 168: 272-278, 2021 Jan 31.
Article in English | MEDLINE | ID: covidwho-1065145

ABSTRACT

SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Exoribonucleases/antagonists & inhibitors , Ritonavir/pharmacology , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/virology , Catalytic Domain , Computer Simulation , Drug Evaluation, Preclinical , Drug Synergism , Drug Therapy, Combination , Exoribonucleases/chemistry , Exoribonucleases/genetics , Genome, Viral/drug effects , Humans , Molecular Dynamics Simulation , Pandemics , Ritonavir/administration & dosage , Ritonavir/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Virus Replication/drug effects
12.
Int J Biol Macromol ; 168: 272-278, 2021 Jan 31.
Article in English | MEDLINE | ID: covidwho-987985

ABSTRACT

SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Exoribonucleases/antagonists & inhibitors , Ritonavir/pharmacology , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/virology , Catalytic Domain , Computer Simulation , Drug Evaluation, Preclinical , Drug Synergism , Drug Therapy, Combination , Exoribonucleases/chemistry , Exoribonucleases/genetics , Genome, Viral/drug effects , Humans , Molecular Dynamics Simulation , Pandemics , Ritonavir/administration & dosage , Ritonavir/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Virus Replication/drug effects
13.
Clin Epigenetics ; 12(1): 118, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-695596

ABSTRACT

Coronaviruses (CoVs) are highly diverse single-stranded RNA viruses owing to their susceptibility to numerous genomic mutations and recombination. Such viruses involve human and animal pathogens including the etiologic agents of acute respiratory tract illnesses: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the highly morbific SARS-CoV-2. Coronavirus disease 2019 (COVID-19), an emerging disease with a quick rise in infected cases and deaths, was recently identified causing a worldwide pandemic. COVID-19 disease outcomes were found to increase in elderly and patients with a compromised immune system. Evidences indicated that the main culprit behind COVID-19 deaths is the cytokine storm, which is illustrated by an uncontrolled over-production of soluble markers of inflammation. The regulation process of coronavirus pathogenesis through molecular mechanism comprise virus-host interactions linked to viral entry, replication and transcription, escape, and immune system control. Recognizing coronavirus infections and COVID-19 through epigenetics lens will lead to potential alteration in gene expression thus limiting coronavirus infections. Focusing on epigenetic therapies reaching clinical trials, clinically approved epigenetic-targeted agents, and combination therapy of antivirals and epigenetic drugs is currently considered an effective and valuable approach for viral replication and inflammatory overdrive control.


Subject(s)
Betacoronavirus , Coronavirus Infections , Epigenomics/methods , Pandemics , Pneumonia, Viral , Betacoronavirus/genetics , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Discovery/methods , Genome, Viral/drug effects , Humans , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2
14.
Viruses ; 12(7)2020 06 28.
Article in English | MEDLINE | ID: covidwho-627994

ABSTRACT

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), and norovirus (NV) are highly contagious pathogens that threaten human health. Here we focused on the antiviral potential of the medicinal herb, Saxifraga spinulosa (SS). Water-soluble extracts of SS were prepared, and their virus-inactivating activity was evaluated against the human virus pathogens SARS-CoV-2 and IAV; we also examined virucidal activity against feline calicivirus and murine norovirus, which are surrogates for human NV. Among our findings, we found that SS-derived gallocatechin gallate compounds were capable of inactivating all viruses tested. Interestingly, a pyrogallol-enriched fraction (Fr 1C) inactivated all viruses more rapidly and effectively than did any of the component compounds used alone. We found that 25 µg/mL of Fr 1C inactivated >99.6% of SARS-CoV-2 within 10 s (reduction of ≥2.33 log10 TCID50/mL). Fr 1C resulted in the disruption of viral genomes and proteins as determined by gel electrophoresis, electron microscopy, and reverse transcription-PCR. Taken together, our results reveal the potential of Fr 1C for development as a novel antiviral disinfectant.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Influenza A virus/drug effects , Norovirus/drug effects , Plant Extracts/pharmacology , Plants, Medicinal , Saxifragaceae , Betacoronavirus/ultrastructure , Calicivirus, Feline/drug effects , Electrophoresis, Polyacrylamide Gel , Genome, Viral/drug effects , Hemagglutination Tests , Humans , Microscopy, Electron, Transmission , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Viral Proteins/drug effects
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