scholarly journals Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Kunal Dutta ◽  
Sergey Shityakov ◽  
Olga Morozova ◽  
Ibrahim Khalifa ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Polymerase Activity ◽  
Amino Acid Residues ◽  
Rna Dependent Rna Polymerase ◽  
Recent Emergence ◽  
Novel Coronavirus

Recent emergence of novel coronavirus (SARS-CoV-2) in Wuhan, China has resulted more than 14,510 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between well-known antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRp of the HCV can efficiently bind to RdRp of the SARS-CoV-2 (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of only 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for SARS-CoV-2. In addition, beclabuvir also shows better binding free energy (ΔGvina = 9.7 kcal mol-1) than that of the Thumb 1 domain of RdRp of HCV (ΔGvina = 7.7 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity existed within 549 to 776 amino acid residues of RdRp. Moreover, major interacting amino acid residues were I591, Y621, C624, D625, A690, N693, L760, D762, D763 and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRp which is essential for viral RNA synthesis. In conclusion, results suggest beclabuvir has high therapeutic potential as an anti-SARS-CoV-2 drug.

scholarly journals Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Kunal Dutta ◽  
Sergey Shityakov ◽  
Olga Morozova ◽  
Ibrahim Khalifa ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Binding Free Energy ◽  
Polymerase Activity ◽  
Amino Acid Residues ◽  
Rna Dependent Rna Polymerase ◽  
Recent Emergence ◽  
Novel Coronavirus ◽  
Major Amino Acid

Recent emergence of novel coronavirus (SARS-CoV-2) all over the world has resulted more than 33,106 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between FDA-approved antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRpHCV can efficiently bind to RdRp SARS-CoV-2 (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for binding of beclabuvir to RdRpSARS-CoV-2. In addition, beclabuvir has also shown better binding free energy with RdRpSARS-CoV-2 (ΔGvina = -8.0 kcal mol-1) than that observed with the Thumb 1 domain of RdRpHCV (ΔGvina = -7.1 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity exists within 549th to 776th amino acid residues of RdRpSARS-CoV, where the major amino acid residues interacting being I591, Y621, C624, D625, A690, N693, L760, D762, D763, and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRpSARS-CoV-2, the enzyme essential for viral RNA synthesis. In conclusion, results suggest beclabuvir may serve as an anti-SARS-CoV-2 drug.

scholarly journals Suramin, Penciclovir and Anidulafungin bind nsp12, which governs the RNA-dependent-RNA polymerase activity of SARS-CoV-2, with higher interaction energy than Remdesivir, indicating potential in the treatment of Covid-19

2020 ◽  
Author(s):  
Sanjay Kumar Dey ◽  
Manisha Saini ◽  
Chetna Dhembla ◽  
Shruti Bhatt ◽  
A. Sai Rajesh ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Drug Repositioning ◽  
Polymerase Activity ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Rna Dependent Rna Polymerase ◽  
Rna Polymerase Activity

Structured abstract:Introduction: COVID-19, for which no vaccine or confirmed therapeutic agents are available, has claimed over 7,30,000 lives globally. A feasible and quicker method to resolve this problem may be ‘drug repositioning’.Areas covered: We investigated selected FDA and WHO-EML approved drugs based on their previously promising potential as antivirals, antibacterials or antifungals. These drugs were docked onto the three-dimensional structure of nsp12 protein, which reigns the RNA-dependent RNA polymerase activity of SARS-CoV-2 and is one of the major therapeutic targets for corona viruses. Inhibitor-protein complexes were also subjected to molecular dynamics simulation. The binding energies and the mode of interaction of the active site of the protein with the drugs were evaluated.Results: Suramin, Penciclovir and Anidulafungin were found to bind to nsp12 with similar binding energies as that of Remdesivir, which is currently being used in the treatment of COVID-19. In addition, recent experimental evidences indicate that these drugs exhibit antiviral efficacy against SARS-CoV-2. Thus, they might have a prospective therapeutic potential against the key viral enzyme.Expert opinion: Repurposed drugs will provide viable options for the treatment of COVID-19 and insight into the molecular mechanisms by which these potential drug candidates exhibit anti-SARSCoV-2 activity.

scholarly journals Susceptibility of spike glycoprotein and RNA-dependent RNA polymerase of SARS-CoV-2 to mutation: in silico structural dynamics study

2021 ◽  
Vol 9 (4) ◽  
pp. 148-152
Author(s):  
Toluwase Hezekiah Fatoki ◽  
Jude Akinyelu ◽  
Oluwafijimi Yomi Adetuyi ◽  
Temitope Olawale Jeje ◽  
Uchechukwu Nebo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
In Silico ◽  
Structural Flexibility ◽  
Amino Acid Residues ◽  
Spike Glycoprotein ◽  
Rna Dependent Rna Polymerase ◽  
Evolutionary Changes ◽  
Fast Pace ◽  
Structural Fluctuations

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a microorganism that causes coronavirus disease 2019 (COVID-19). Mutations affect evolutionary conservation of microorganisms. The fast pace evolutionary changes are currently affecting pathogenicity of SARS-CoV-2. In this study, the structural fluctuations of the amino acid residues in the spike glycoprotein and RNA-dependent RNA polymerase (nsp12) of SARS-CoV-2 were investigated by in silico approach using structural flexibility dynamics to decipher susceptibility to mutation. The result of this study implicated key amino acid residues (with rmsf) which could be very susceptible to mutation, which include residues 50 (3.79 Å), 119 (4.56 Å), 120 (3.53 Å), 220 (3.84 Å), 265 (4.31 Å) of RNA-dependent RNA polymerase (nsp12), as well as residues 477 (4.21 Å), 478 (4.82 Å), 479 (5.40 Å), 481 (5.94 Å), 560 (4.63 Å), 704 (4.02 Å), 848 (4.58 Å), 1144 (4.56 Å) and 1147 (4.61 Å) of spike glycoprotein. The SARS-CoV-2 mutations destabilized the overall protein structure in multiples of amino acid residues which could interfere with active site leading to insensitivity or resistance to the inhibitors. Mutation T478K of Spike glycoprotein showed the highest deviation in the structure. Overall, spike glycoprotein has the highest number of mutations, and these variants could increase the risk to human health if not mitigated in the population.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Goran Kokic ◽  
Hauke S. Hillen ◽  
Dimitry Tegunov ◽  
Christian Dienemann ◽  
Florian Seitz ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Rna Polymerase ◽  
Binding Site ◽  
Molecular Mechanism ◽  
Active Center ◽  
Rna Synthesis ◽  
Active Form ◽  
Nucleoside Triphosphate ◽  
Rna Dependent Rna Polymerase ◽  
Cryo Electron Microscopy

AbstractRemdesivir 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 3ʹ-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 3ʹ-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 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.

scholarly journals Initiation of (—)-Strand RNA Synthesis Catalyzed by the BMV RNA-Dependent RNA Polymerase: Synthesis of Oligonucleotides

Virology ◽  
1997 ◽  
Vol 228 (1) ◽  
pp. 121
Author(s):  
Jin-Hua Sun ◽  
Scott Adkins ◽  
Greta Faurote ◽  
C.Cheng Kao
Keyword(s):  
Rna Polymerase ◽  
Rna Synthesis ◽  
Rna Dependent Rna Polymerase

scholarly journals Ubiquitination Is Essential for Avibirnavirus Replication by Supporting VP1 Polymerase Activity

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Huansheng Wu ◽  
Liuyuan Shi ◽  
Yina Zhang ◽  
Xiran Peng ◽  
Tuyuan Zheng ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Virus Replication ◽  
Mutation Screening ◽  
Polymerase Activity ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Rna Dependent Rna Polymerase ◽  
Ubiquitin Chain ◽  
Vp1 Protein ◽  
C Terminus

ABSTRACTUbiquitination is critical for several cellular physical processes. However, ubiquitin modification in virus replication is poorly understood. Therefore, the present study aimed to determine the presence and effect of ubiquitination on polymerase activity of viral protein 1 (VP1) of avibirnavirus. We report that the replication of avibirnavirus is regulated by ubiquitination of its VP1 protein, the RNA-dependent RNA polymerase of infectious bursal disease virus (IBDV).In vivodetection revealed the ubiquitination of VP1 protein in IBDV-infected target organs and different cells but not in purified IBDV particles. Further analysis of ubiquitination confirms that VP1 is modified by K63-linked ubiquitin chain. Point mutation screening showed that the ubiquitination site of VP1 was at the K751 residue in the C terminus. The K751 ubiquitination is independent of VP1’s interaction with VP3 and eukaryotic initiation factor 4A II. Polymerase activity assays indicated that the K751 ubiquitination at the C terminus of VP1 enhanced its polymerase activity. The K751-to-R mutation of VP1 protein did not block the rescue of IBDV but decreased the replication ability of IBDV. Our data demonstrate that the ubiquitination of VP1 is crucial to regulate its polymerase activity and IBDV replication.IMPORTANCEAvibirnavirus protein VP1, the RNA-dependent RNA polymerase, is responsible for IBDV genome replication, gene expression, and assembly. However, little is known about its chemical modification relating to its polymerase activity. In this study, we revealed the molecular mechanism of ubiquitin modification of VP1 via a K63-linked ubiquitin chain during infection. Lysine (K) residue 751 at the C terminus of VP1 is the target site for ubiquitin, and its ubiquitination is independent of VP1’s interaction with VP3 and eukaryotic initiation factor 4A II. The K751 ubiquitination promotes the polymerase activity of VP1 and unubiquitinated VP1 mutant IBDV significantly impairs virus replication. We conclude that VP1 is the ubiquitin-modified protein and reveal the mechanism by which VP1 promotes avibirnavirus replication.

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