scholarly journals Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sten Ilmjärv ◽  
Fabien Abdul ◽  
Silvia Acosta-Gutiérrez ◽  
Carolina Estarellas ◽  
Ioannis Galdadas ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Molecular Modelling ◽  
Spike Protein ◽  
Genome Sequences ◽  
Viral Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
High Quality

AbstractThe D614G mutation in the Spike protein of the SARS-CoV-2 has effectively replaced the early pandemic-causing variant. Using pseudotyped lentivectors, we confirmed that the aspartate replacement by glycine in position 614 is markedly more infectious. Molecular modelling suggests that the G614 mutation facilitates transition towards an open state of the Spike protein. To explain the epidemiological success of D614G, we analysed the evolution of 27,086 high-quality SARS-CoV-2 genome sequences from GISAID. We observed striking coevolution of D614G with the P323L mutation in the viral polymerase. Importantly, the exclusive presence of G614 or L323 did not become epidemiologically relevant. In contrast, the combination of the two mutations gave rise to a viral G/L variant that has all but replaced the initial D/P variant. Our results suggest that the P323L mutation, located in the interface domain of the RNA-dependent RNA polymerase, is a necessary alteration that led to the epidemiological success of the present variant of SARS-CoV-2. However, we did not observe a significant correlation between reported COVID-19 mortality in different countries and the prevalence of the Wuhan versus G/L variant. Nevertheless, when comparing the speed of emergence and the ultimate predominance in individual countries, it is clear that the G/L variant displays major epidemiological supremacy over the original variant.

scholarly journals Epidemiologically most successful SARS-CoV-2 variant: concurrent mutations in RNA-dependent RNA polymerase and spike protein

2020 ◽  
Author(s):  
Sten Ilmjärv ◽  
Fabien Abdul ◽  
Silvia Acosta-Gutiérrez ◽  
Carolina Estarellas ◽  
Ioannis Galdadas ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Molecular Modelling ◽  
Spike Protein ◽  
Genome Sequences ◽  
Viral Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
High Quality

The D614G mutation of the Spike protein is thought to be relevant for SARS-CoV-2 infection. Here we report biological and epidemiological aspects of this mutation. Using pseudotyped lentivectors, we were able to confirm that the G614 variant of the Spike protein is markedly more infectious than the ancestral D614 variant. We demonstrate by molecular modelling that the replacement of aspartate by glycine in position 614 facilitates the transition towards an open state of the Spike protein. To understand whether the increased infectivity of the D614 variant explains its epidemiological success, we analysed the evolution of 27,086 high-quality SARS-CoV-2 genome sequences from GISAID. We observed striking coevolution of D614G with the P323L mutation in the viral polymerase. Importantly, exclusive presence of G614 or L323 did not become epidemiologically relevant. In contrast, the combination of the two mutations gave rise to a viral G/L variant that has all but replaced the initial D/P variant. There was no significant correlation between reported COVID mortality in different countries and the prevalence of the Wuhan versus G/L variant. However, when comparing the speed of emergence and the ultimate predominance in individual countries, the G/L variant displays major epidemiological supremacy. Our results suggest that the P323L mutation, located in the interface domain of the RNA-dependent RNA polymerase (RdRp), is a necessary alteration that led to the epidemiological success of the present variant of SARS-CoV-2.

scholarly journals SARS-CoV-2 Spike Protein and RNA Dependent RNA Polymerase as Targets for Drug and Vaccine Development: A Review

2021 ◽  
Author(s):  
Yusuf Muhammed ◽  
Abduljalal Yusuf Nadabo ◽  
Mkpouto Pius ◽  
Bashiru Sani ◽  
Jafar Usman ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Vaccine Development ◽  
Spike Protein ◽  
Rna Dependent Rna Polymerase

scholarly journals Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Alexander J. McAuley ◽  
Michael J. Kuiper ◽  
Peter A. Durr ◽  
Matthew P. Bruce ◽  
Jennifer Barr ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Experimental Evidence ◽  
In Silico ◽  
Cleavage Site ◽  
Spike Protein ◽  
Rna Dependent Rna Polymerase ◽  
Virus Isolates

Abstract The ‘D614G’ mutation (Aspartate-to-Glycine change at position 614) of the SARS-CoV-2 spike protein has been speculated to adversely affect the efficacy of most vaccines and countermeasures that target this glycoprotein, necessitating frequent vaccine matching. Virus neutralisation assays were performed using sera from ferrets which received two doses of the INO-4800 COVID-19 vaccine, and Australian virus isolates (VIC01, SA01 and VIC31) which either possess or lack this mutation but are otherwise comparable. Through this approach, supported by biomolecular modelling of this mutation and the commonly-associated P314L mutation in the RNA-dependent RNA polymerase, we have shown that there is no experimental evidence to support this speculation. We additionally demonstrate that the putative elastase cleavage site introduced by the D614G mutation is unlikely to be accessible to proteases.

scholarly journals 3D Molecular Modelling Study of the H7N9 RNA-Dependent RNA Polymerase as an Emerging Pharmacological Target

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Dimitrios Vlachakis ◽  
Argiro Karozou ◽  
Sophia Kossida
Keyword(s):  
Rna Polymerase ◽  
Molecular Modelling ◽  
Homology Modelling ◽  
Complex Structure ◽  
Rna Dependent Rna Polymerase ◽  
Major Drawback ◽  
Virus Rna ◽  
Modelling Techniques ◽  
Dynamics Simulations ◽  
Structural Insights

Currently not much is known about the H7N9 strain, and this is the major drawback for a scientific strategy to tackle this virus. Herein, the 3D complex structure of the H7N9 RNA-dependent RNA polymerase has been established using a repertoire of molecular modelling techniques including homology modelling, molecular docking, and molecular dynamics simulations. Strikingly, it was found that the oligonucleotide cleft and tunnel in the H7N9 RNA-dependent RNA polymerase are structurally very similar to the corresponding region on the hepatitis C virus RNA-dependent RNA polymerase crystal structure. A direct comparison and a 3D postdynamics analysis of the 3D complex of the H7N9 RNA-dependent RNA polymerase provide invaluable clues and insight regarding the role and mode of action of a series of interacting residues on the latter enzyme. Our study provides a novel and efficiently intergraded platform with structural insights for the H7N9 RNA-dependent RNA Polymerase. We propose that future use and exploitation of these insights may prove invaluable in the fight against this lethal, ongoing epidemic.

scholarly journals Redefining the medicago sativa alphapartitivirus genome sequences

2019 ◽  
Author(s):  
Nicolás Bejerman ◽  
Debat Humberto ◽  
Verónica Trucco ◽  
Soledad de Breuil ◽  
Sergio Lenardon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
Medicago Sativa ◽  
De Novo ◽  
Gene Products ◽  
Rt Pcr ◽  
Genome Sequences ◽  
Rna Dependent Rna Polymerase ◽  
Broad Distribution ◽  
Encoding Gene

AbstractIn alfalfa samples analyzed by hightroughput sequencing, four de novo assembled contigs encoding gene products showing identities to alphapartitiviruses proteins were found based on BlastX analysis. The predicted amino acid (aa) sequences of two contigs presented 99-100% identity to the RNA-dependent RNA polymerase (RdRp) and the capsid protein (CP) of the recently reported medicago sativa alphapartitivirus 1 (MsAPV1). In addition, the remaining two contigs shared only 56% (CP) and 70% (RdRp) pairwise aa identity with the proteins of MsAPV1, suggesting that these samples presented also a novel Alphapartitivirus species. Further analyses based on complete genome segments termini and the presence/absence of alphapartitivirus RNA in several samples and public alfalfa RNA datasets corroborated the identification of two different alphapartitivirus members. Our results also likely indicate that the reported MsAPV1 genome was previously reconstructed with genome segments of two different alphapartitiviruses. Overall, we not only revisited the MsAPV1 genome sequence but also report a new tentative alphapartitivirus species, which we propose the name medicago sativa alphapartitivirus 2. In addition, the RT-PCR detection of both MsAPV1 and MsAPV2 in several alfalfa cultivars suggests a broad distribution of both viruses.

scholarly journals A Narnavirus -Like Element from the Trypanosomatid Protozoan Parasite Leptomonas seymouri

2016 ◽  
Vol 4 (4) ◽  
Author(s):  
Lon-Fye Lye ◽  
Natalia S. Akopyants ◽  
Deborah E. Dobson ◽  
Stephen M. Beverley
Keyword(s):  
Rna Polymerase ◽  
Rna Virus ◽  
Protozoan Parasite ◽  
Database Search ◽  
Genome Sequences ◽  
Rna Dependent Rna Polymerase ◽  
First Report

Genome sequences were determined for a novel RNA virus, Leptomonas seymouri Narna-like virus 1 (LepseyNLV1). A 2.9-kb segment encodes an RNA-dependent RNA polymerase (RdRp), while a smaller 1.5-kb segment showed no database search matches. This is the first report of bisegmented Narnaviridae from insect trypanosomatids.

scholarly journals Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19

2020 ◽  
Vol 9 (4) ◽  
pp. 1131 ◽  
Author(s):  
Jiansheng Huang ◽  
Wenliang Song ◽  
Hui Huang ◽  
Quancai Sun
Keyword(s):  
Rna Polymerase ◽  
The United States ◽  
Spike Protein ◽  
Therapeutic Approaches ◽  
Rna Dependent Rna Polymerase ◽  
S Protein ◽  
Functional Relationships ◽  
Human Lung Cells ◽  
Novel Coronavirus

An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.

scholarly journals A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity

2020 ◽  
Vol 9 (8) ◽  
pp. 2399
Author(s):  
Jung Sun Min ◽  
Geon-Woo Kim ◽  
Sunoh Kwon ◽  
Young-Hee Jin
Keyword(s):  
Rna Polymerase ◽  
Polymerase Activity ◽  
Reporter Assay ◽  
Reporter System ◽  
Viral Polymerase ◽  
Rdrp Activity ◽  
Rna Dependent Rna Polymerase ◽  
Polymerase Inhibitors ◽  
Plasmid Construct ◽  
A Cell

Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19) are emerging zoonotic diseases caused by coronavirus (CoV) infections. The viral RNA-dependent RNA polymerase (RdRp) has been suggested as a valuable target for antiviral therapeutics because the sequence homology of CoV RdRp is highly conserved. We established a cell-based reporter assay for MERS-CoV RdRp activity to test viral polymerase inhibitors. The cell-based reporter system was composed of the bicistronic reporter construct and the MERS-CoV nsp12 plasmid construct. Among the tested nine viral polymerase inhibitors, ribavirin, sofosbuvir, favipiravir, lamivudine, zidovudine, valacyclovir, vidarabine, dasabuvir, and remdesivir, only remdesivir exhibited a dose-dependent inhibition. Meanwhile, the Z-factor and Z′-factor of this assay for screening inhibitors of MERS-CoV RdRp activity were 0.778 and 0.782, respectively. Ribavirin and favipiravir did not inhibit the MERS-CoV RdRp activity, and non-nucleoside HCV RdRp inhibitor, dasabuvir, partially inhibited MERS-CoV RdRp activity. Taken together, the cell-based reporter assay for MERS-CoV RdRp activity confirmed remdesivir as a direct inhibitor of MERS-CoV RdRp in cells. A cell-based MERS-CoV RdRp activity reporter assay is reliable and accurate for screening MERS-CoV RdRp-specific inhibitors. It may provide a valuable platform for developing antiviral drugs for emerging CoV infections.

scholarly journals Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase

2021 ◽  
Author(s):  
William M Showers ◽  
Sonia M Leach ◽  
Katerina Kechris ◽  
Michael Strong
Keyword(s):  
Rna Polymerase ◽  
High Frequency ◽  
Drug Targets ◽  
Spike Protein ◽  
Structural Level ◽  
Receptor Binding Domain ◽  
Rna Dependent Rna Polymerase ◽  
Public Health Strategies ◽  
Further Development ◽  
Over Time

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences for the spike proteins and RNA-dependent RNA polymerase proteins were downloaded from the GISAID database, aligned, and the variants identified. Polymorphisms in the protein sequence were investigated at the protein structural level and examined longitudinally in order to identify sequence and strain variants that are emerging over time. Our analysis revealed a group of variants in the spike protein and the polymerase complex that appeared in August, and account for around five percent of the genomes analyzed up to the last week of October. A structural analysis also facilitated investigation of several unique variants in the receptor binding domain and the N-terminal domain of the spike protein, with high-frequency mutations occurring more commonly in these regions. The identification of new variants emphasizes the need for further study on the effects of these mutations and the implications of their increased prevalence, particularly as these mutations may impact vaccine or therapeutic efficacy.

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