scholarly journals TMPRSS2 and RNA-Dependent RNA Polymerase Are Effective Targets of Therapeutic Intervention for Treatment of COVID-19 Caused by SARS-CoV-2 Variants (B.1.1.7 and B.1.351)

2021 ◽  
Author(s):  
Jihye Lee ◽  
JinAh Lee ◽  
Hyeon Ju Kim ◽  
Meehyun Ko ◽  
Youngmee Jee ◽  
...  
Keyword(s):  
Public Health ◽  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Rna Polymerase ◽  
Causative Agent ◽  
Therapeutic Intervention ◽  
Human Society ◽  
Rna Dependent Rna Polymerase ◽  
Global Problems

The coronavirus disease 2019 (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 agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging and threatening the efficacy of vaccines and monoclonal antibodies.

scholarly journals Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

2020 ◽  
Vol 295 (20) ◽  
pp. 6785-6797 ◽  
Author(s):  
Calvin J. Gordon ◽  
Egor P. Tchesnokov ◽  
Emma Woolner ◽  
Jason K. Perry ◽  
Joy Y. Feng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Lassa Virus ◽  
Nonstructural Proteins ◽  
Rna Dependent Rna Polymerase ◽  
Direct Acting Antiviral ◽  
Nucleotide Analogue ◽  
Direct Acting

Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2′-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.

scholarly journals Combined Homeopathy and Allopathy Treatment for COVID-19: A Review

2020 ◽  
pp. S38-S45
Author(s):  
Md Irfanul Haque ◽  
Aqib Adnan Shafin ◽  
Md Mahmud
Keyword(s):  
Public Health ◽  
Severe Acute Respiratory Syndrome ◽  
Infectious Diseases ◽  
World Health Organization ◽  
Causative Agent ◽  
Public Health Emergency ◽  
World Health ◽  
Treatment Approaches ◽  
Novel Virus ◽  
Health Organization

At the end of 2019, an outburst of a novel virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was observed in Wuhan, China. World Health Organization proclaimed this upsurge as a Public Health Emergency of International Concern on 30th January 2020. In this article, epidemiology, the causative agent, pathogenesis of SARS-CoV-2 and its treatment approaches like homeopathy and allopathy are reviewed. However, our main focus was to collect and visualize some data which bring evidence that combined homeopathy and allopathy treatment can help to cure COVID-19. Bangladesh Journal of Infectious Diseases, October 2020;7(suppl_2):S38-S45

scholarly journals Prediction of Small Molecule Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus-2 RNA-dependent RNA Polymerase

ACS Omega ◽  
2020 ◽  
Vol 5 (29) ◽  
pp. 18356-18366 ◽  
Author(s):  
Mohammed Ahmad ◽  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Satish Tiwari ◽  
Deepsikha Kar ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Rna Polymerase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Rna Dependent Rna Polymerase

scholarly journals Early combination treatment with existing HIV antivirals: an effective treatment for COVID-19? 

2020 ◽  
Author(s):  
Roberto Nico Dallocchio ◽  
Alessandro Dessì ◽  
Andrea De Vito ◽  
Giovanna Delogu ◽  
Pier Andrea ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
Rna Polymerase ◽  
Protease Inhibitor ◽  
Combination Treatment ◽  
Binding Sites ◽  
Nucleoside Analogues ◽  
Rna Dependent Rna Polymerase ◽  
Protein Pocket

Abstract Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better Ki for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RNA-dependent RNA polymerase in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. The combination of a protease inhibitor and two nucleoside analogues should be evaluated in clinical trials for the treatment of COVID-19.

scholarly journals Review on Chronic Impacts of Carbon Monoxide Intoxication on Some Routine Vitreous and Blood Investigations

2020 ◽  
Vol 5 (1) ◽  
pp. 16-25
Author(s):  
Eni-yimini S. Agoro ◽  
◽  
Ebiere N. Ben-Wakama ◽  
Peter W. Alabrah ◽  
◽  
...  
Keyword(s):  
Public Health ◽  
Carbon Monoxide ◽  
Chronic Diseases ◽  
Causative Agent ◽  
Preventive Medicine ◽  
Therapeutic Intervention ◽  
Disease Diagnosis ◽  
The Body ◽  
Haematological Parameters ◽  
Co Intoxication

Carbon monoxide (CO) is a toxic gas produced as a result of incomplete combustion of organic materials. The source of CO production is very common especially in nations that depend on power generating sets for electricity. Chronic disease is non-communicable and usually takes a longer time to manifest. Examples are kidney failure, diabetes mellitus, hypertension, cancer, and cardiac arrest. These diseases are now very common in society, not sparing the youthful population that was rare ab initio. The major difficulty in the containment of chronic diseases is the inability to establish a definitive causative agent. The definite causative agent is important in public health and management of chronic diseases. Preventive medicine is anchored on establishing the causative agent of a disease. Without knowing the causative agent of a disease, the path to prevention becomes very cumbersome. The knowledge of the causative agent of a disease is the bedrock of preventive medicine and public health. Several reasons such as lifestyle modification, hereditary, climate change, nutrition or aging have been adduced as the cause of chronic diseases. These reasons are quite weak and not definite. The exact causative agent(s) of chronic diseases is a conundrum that needs a deliberate study and review so as to enhance definite diagnosis, preventive measures and appropriate therapeutic intervention. Measurement of biochemical and haematological parameters are employed in disease diagnosis and management. Alterations of these parameters are used to identify chronic diseases and also form part of an alarm system of a potential breakdown of the normal functioning of the body. The effect of chronic CO intoxication on these parameters could be of importance in establishing causative agent(s) of diseases that are for long opaque and non-definite. This review was therefore designed to interrogate various narratives, meta-analysis, and researches on this subject. Explicit knowledge of the pattern or presentation of biochemical and haematological parameters arising from chronic CO intoxication could be of great importance in preventive medicine, disease diagnosis and appropriate therapeutic intervention.

scholarly journals Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication-transcription complex

2020 ◽  
Author(s):  
James Chen ◽  
Brandon Malone ◽  
Eliza Llewellyn ◽  
Michael Grasso ◽  
Patrick M. M. Shelton ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Rna Polymerase ◽  
Viral Replication ◽  
Causative Agent ◽  
Structural Basis ◽  
Nucleic Acid Binding ◽  
Electron Microscopic ◽  
Rna Dependent Rna Polymerase ◽  
Therapeutic Development ◽  
Rna Polymerase Holoenzyme

SUMMARYSARS-CoV-2 is the causative agent of the 2019-2020 pandemic. The SARS-CoV-2 genome is replicated-transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp82/nsp12) along with a cast of accessory factors. One of these factors is the nsp13 helicase. Both the holo-RdRp and nsp13 are essential for viral replication and are targets for treating the disease COVID-19. Here we present cryo-electron microscopic structures of the SARS-CoV-2 holo-RdRp with an RNA template-product in complex with two molecules of the nsp13 helicase. The Nidovirus-order-specific N-terminal domains of each nsp13 interact with the N-terminal extension of each copy of nsp8. One nsp13 also contacts the nsp12-thumb. The structure places the nucleic acid-binding ATPase domains of the helicase directly in front of the replicating-transcribing holo-RdRp, constraining models for nsp13 function. We also observe ADP-Mg2+ bound in the nsp12 N-terminal nidovirus RdRp-associated nucleotidyltransferase domain, detailing a new pocket for anti-viral therapeutic development.

scholarly journals RNA-dependent RNA polymerase complex of Brome mosaic virus: analysis of the molecular structure with monoclonal antibodies

2002 ◽  
Vol 83 (11) ◽  
pp. 2879-2890 ◽  
Author(s):  
Koji Dohi ◽  
Kazuyuki Mise ◽  
Iwao Furusawa ◽  
Tetsuro Okuno
Keyword(s):  
Monoclonal Antibodies ◽  
Rna Polymerase ◽  
Mosaic Virus ◽  
Membrane Structure ◽  
Brome Mosaic Virus ◽  
Host Cells ◽  
Intermediate Region ◽  
Rna Dependent Rna Polymerase ◽  
Cellular Factors ◽  
Membrane Bound

Viral RNA-dependent RNA polymerase (RdRp) plays crucial roles in the genomic replication and subgenomic transcription of Brome mosaic virus (BMV), a positive-stranded RNA plant virus. BMV RdRp is a complex of virus-encoded 1a and 2a proteins and some cellular factors, and associates with the endoplasmic reticulum at an infection-specific structure in the cytoplasm of host cells. In this study, we investigate the gross structure of the active BMV RdRp complex using monoclonal antibodies raised against the 1a and 2a proteins. Immunoprecipitation experiments showed that the intermediate region between the N-terminal methyltransferase-like domain and the C-terminal helicase-like domain of 1a protein, and the N terminus region of 2a protein are exposed on the surface of the solubilized RdRp complex. Inhibition assays for membrane-bound RdRp suggested that the intermediate region between the methyltransferase-like and the helicase-like domains of 1a protein is located at the border of the region buried within a membrane structure or with membrane-associated material.

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