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1.
Molecules ; 27(3)2022 Jan 26.
Article in English | MEDLINE | ID: covidwho-1648677

ABSTRACT

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.


Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/drug effects , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Pyrimidines/pharmacology , Triazoles/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Amides/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Catalytic Domain/drug effects , Computational Biology/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pyrazines/pharmacology , Pyrimidines/chemistry , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/drug effects , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Triazoles/chemistry , Virus Replication/drug effects
2.
Cell Rep ; 37(4): 109882, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1525720

ABSTRACT

Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Viral Proteins/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/drug therapy , Cryoelectron Microscopy , Humans , RNA, Viral/chemistry , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , Virus Replication/drug effects
3.
Antiviral Res ; 196: 105209, 2021 12.
Article in English | MEDLINE | ID: covidwho-1520691

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC50 value of 1.41 µM and highest selectivity index (CC50/EC50) (above 70.92). Furthermore, our data suggests that 4-46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4-46b and 6-72-2a exhibit EC50 values of 1.13 µM and 0.94 µM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4-46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.


Subject(s)
Acetamides/pharmacology , COVID-19/drug therapy , RNA-Dependent RNA Polymerase , Antiviral Agents/pharmacology , Drug Delivery Systems , Humans , RNA, Viral/biosynthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Viral Proteins/antagonists & inhibitors , Viral Proteins/drug effects , Virus Replication/drug effects
4.
Microbiol Spectr ; 9(1): e0047221, 2021 09 03.
Article in English | MEDLINE | ID: covidwho-1352541

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative agent of the coronavirus disease 2019 (COVID-19) pandemic, and the development of therapeutic interventions is urgently needed. So far, monoclonal antibodies and drug repositioning are the main methods for drug development, and this effort was partially successful. Since the beginning of the COVID-19 pandemic, the emergence of SARS-CoV-2 variants has been reported in many parts of the world, and the main concern is whether the current vaccines and therapeutics are still effective against these variant viruses. Viral entry and viral RNA-dependent RNA polymerase (RdRp) are the main targets of current drug development; therefore, the inhibitory effects of transmembrane serine protease 2 (TMPRSS2) and RdRp inhibitors were compared among the early SARS-CoV-2 isolate (lineage A) and the two recent variants (lineage B.1.1.7 and lineage B.1.351) identified in the United Kingdom and South Africa, respectively. Our in vitro analysis of viral replication showed that the drugs targeting TMPRSS2 and RdRp are equally effective against the two variants of concern. IMPORTANCE The COVID-19 pandemic is causing unprecedented global problems in both public health and human society. While some vaccines and monoclonal antibodies were successfully developed very quickly and are currently being used, numerous variants of the causative SARS-CoV-2 are emerging and threatening the efficacy of vaccines and monoclonal antibodies. In order to respond to this challenge, we assessed antiviral efficacy of small-molecule inhibitors that are being developed for treatment of COVID-19 and found that they are still very effective against the SARS-CoV-2 variants. Since most small-molecule inhibitors target viral or host factors other than the mutated sequence of the viral spike protein, they are expected to be potent control measures against the COVID-19 pandemic.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Serine Endopeptidases/drug effects , Animals , Antiviral Agents/therapeutic use , Chlorocebus aethiops , Humans , South Africa , United Kingdom , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
5.
Nat Commun ; 12(1): 279, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-1026823

ABSTRACT

Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3'-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3'-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Aptamers, Nucleotide , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/drug effects , Nucleotides , RNA, Viral , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/enzymology , Virus Replication/drug effects
6.
Comput Biol Med ; 124: 103936, 2020 09.
Article in English | MEDLINE | ID: covidwho-679767

ABSTRACT

Virtual screening of phytochemicals was performed through molecular docking, simulations, in silico ADMET and drug-likeness prediction to identify the potential hits that can inhibit the effects of SARS-CoV-2. Considering the published literature on medicinal importance, 154 phytochemicals with analogous structure from limonoids and triterpenoids were selected to search potential inhibitors for the five therapeutic protein targets of SARS-CoV-2, i.e., 3CLpro (main protease), PLpro (papain-like protease), SGp-RBD (spike glycoprotein-receptor binding domain), RdRp (RNA dependent RNA polymerase) and ACE2 (angiotensin-converting enzyme 2). The in silico computational results revealed that the phytochemicals such as glycyrrhizic acid, limonin, 7-deacetyl-7-benzoylgedunin, maslinic acid, corosolic acid, obacunone and ursolic acid were found to be effective against the target proteins of SARS-CoV-2. The protein-ligand interaction study revealed that these phytochemicals bind with the amino acid residues at the active site of the target proteins. Therefore, the core structure of these potential hits can be used for further lead optimization to design drugs for SARS-CoV-2. Also, the medicinal plants containing these phytochemicals like licorice, neem, tulsi, citrus and olives can be used to formulate suitable therapeutic approaches in traditional medicines.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Limonins/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Triterpenes/pharmacology , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , COVID-19 , Computational Biology , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase , Drug Evaluation, Preclinical , Host Microbial Interactions/drug effects , Humans , Limonins/chemistry , Limonins/pharmacokinetics , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/drug effects , Phytochemicals/chemistry , Phytochemicals/pharmacokinetics , Phytochemicals/pharmacology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Triterpenes/chemistry , Triterpenes/pharmacokinetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , Viral Proteins/chemistry , Viral Proteins/drug effects
7.
J Med Microbiol ; 69(6): 864-873, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-436403

ABSTRACT

Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/enzymology , Betacoronavirus/genetics , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/virology , Drug Evaluation, Preclinical/methods , Drug Synergism , Humans , Molecular Conformation , Pandemics , Phylogeny , Pneumonia, Viral/virology , RNA-Dependent RNA Polymerase/drug effects , Rifampin/pharmacology , SARS-CoV-2 , Sequence Alignment , Sequence Analysis, Protein , Virginiamycin/analogs & derivatives , Virginiamycin/pharmacology , Virus Replication/drug effects
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