scholarly journals Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation

2020 ◽  
Author(s):  
Koichiro Kato ◽  
Teruki Honma ◽  
Kaori Fukuzawa
Keyword(s):  
Rna Polymerase ◽  
Molecular Orbital ◽  
Antiviral Drug ◽  
Molecular Orbital Calculation ◽  
Data Bank ◽  
Rna Dependent Rna Polymerase ◽  
Fragment Molecular Orbital ◽  
Global Pandemic ◽  
The World ◽  
Primer Rna

<p>COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.</p>

scholarly journals Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation

2020 ◽  
Author(s):  
Koichiro Kato ◽  
Teruki Honma ◽  
Kaori Fukuzawa
Keyword(s):  
Rna Polymerase ◽  
Molecular Orbital ◽  
Antiviral Drug ◽  
Molecular Orbital Calculation ◽  
Data Bank ◽  
Rna Dependent Rna Polymerase ◽  
Fragment Molecular Orbital ◽  
Global Pandemic ◽  
The World ◽  
Primer Rna

<p>COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.</p>

scholarly journals Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

2020 ◽  
Author(s):  
Yan Gao ◽  
Liming Yan ◽  
Yucen Huang ◽  
Fengjiang Liu ◽  
Yao Zhao ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Drug Target ◽  
Antiviral Drug ◽  
Central Component ◽  
Rna Dependent Rna Polymerase ◽  
Transcription Machinery ◽  
Global Pandemic ◽  
Novel Coronavirus ◽  
Key Residues ◽  
Insight Into

AbstractA novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-Å. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified β-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.One Sentence SummaryStructure of 2019-nCov RNA polymerase.

scholarly journals Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir

2020 ◽  
Author(s):  
Wanchao Yin ◽  
Chunyou Mao ◽  
Xiaodong Luan ◽  
Dan-Dan Shen ◽  
Qingya Shen ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Virus Disease ◽  
Complex Structure ◽  
Antiviral Drug ◽  
Viral Rna ◽  
Chain Elongation ◽  
Structural Basis ◽  
Rna Dependent Rna Polymerase ◽  
Working Mechanism ◽  
Primer Rna

The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a direct target of the antiviral drug, Remdesivir. Here we report the structure of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50-base template-primer RNA and Remdesivir at a resolution range of 2.5-2.8 Å. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is incorporated into the first replicated base pair and terminates the chain elongation. Our structures provide critical insights into the working mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

scholarly journals Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Science ◽  
2020 ◽  
Vol 368 (6498) ◽  
pp. 1499-1504 ◽  
Author(s):  
Wanchao Yin ◽  
Chunyou Mao ◽  
Xiaodong Luan ◽  
Dan-Dan Shen ◽  
Qingya Shen ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Complex Structure ◽  
Antiviral Drug ◽  
Viral Rna ◽  
Chain Elongation ◽  
Structural Basis ◽  
Rna Dependent Rna Polymerase ◽  
Double Stranded Rna ◽  
Cryo Electron Microscopy ◽  
Primer Rna

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo–electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

scholarly journals SARS-CoV-2 RdRp is a versatile enzyme with proofreading activity and ability to incorporate NHC into RNA by using diphosphate form molnupiravir as a substrate

2021 ◽  
Author(s):  
Maofeng Wang ◽  
Cancan Wu ◽  
Nan Liu ◽  
Fengyu Zhang ◽  
Hongjie Dong ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Drug Development ◽  
Rna Polymerase ◽  
Human Health ◽  
Antiviral Drug ◽  
Polymerase Activity ◽  
Genome Replication ◽  
Rna Dependent Rna Polymerase ◽  
The World ◽  
Rna Polymerase Activity

The coronavirus disease 2019 (COVID-19) has been ravaging throughout the world for almost two years and has severely impaired both human health and the economy. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs the viral RNA-dependent RNA polymerase (RdRp) complex for genome replication and transcription, making RdRp an appealing target for antiviral drug development. Although the structure of the RdRp complex has been determined, the function of RdRp has not been fully characterized. Here we reveal that in addition to RNA dependent RNA polymerase activity, RdRp also shows exoribonuclease activity and consequently proofreading activity. We observed that RdRp and nsp14-ExoN, when combined, exhibit higher proofreading activity compared to RdRp alone. Moreover, RdRp can recognize and utilize nucleoside diphosphate (NDP) as substrate to synthesize RNA and can also incorporate β-d-N4-hydroxycytidine (NHC) into RNA while using diphosphate form molnupiravir as substrate.

scholarly journals Structure of Foot-and-Mouth Disease Virus RNA-dependent RNA Polymerase and Its Complex with a Template-Primer RNA

2004 ◽  
Vol 279 (45) ◽  
pp. 47212-47221 ◽  
Author(s):  
Cristina Ferrer-Orta ◽  
Armando Arias ◽  
Rosa Perez-Luque ◽  
Cristina Escarmís ◽  
Esteban Domingo ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Rna Dependent Rna Polymerase ◽  
Virus Rna ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Primer Rna

scholarly journals High-Precision Atomic Charge Prediction for Protein Systems Using Fragment Molecular Orbital Calculation and Machine Learning

2020 ◽  
Vol 60 (7) ◽  
pp. 3361-3368
Author(s):  
Koichiro Kato ◽  
Tomohide Masuda ◽  
Chiduru Watanabe ◽  
Naoki Miyagawa ◽  
Hideo Mizouchi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Molecular Orbital ◽  
High Precision ◽  
Atomic Charge ◽  
Molecular Orbital Calculation ◽  
Fragment Molecular Orbital

scholarly journals Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1585
Author(s):  
Milan Dejmek ◽  
Eva Konkoľová ◽  
Luděk Eyer ◽  
Petra Straková ◽  
Pavel Svoboda ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Essential Role ◽  
Molecular Targets ◽  
Viral Rna ◽  
Rna Dependent Rna Polymerase ◽  
The World ◽  
Polymerase Inhibitor

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

scholarly journals Vaccines and Treatment of Coronavirus Disease 2019

2020 ◽  
Vol 95 (6) ◽  
pp. 364-369
Author(s):  
Pyoeng Gyun Choe
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Antiviral Agents ◽  
World Health ◽  
Rna Dependent Rna Polymerase ◽  
Global Pandemic ◽  
The World ◽  
Polymerase Inhibitor ◽  
Experimental Treatments ◽  
Health Organization

In December 2019, a new strain of betacoronavirus, severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Subsequently, the virus quickly spread worldwide and the World Health Organization declared COVID-19 a global pandemic on March 11, 2020. In response to the pandemic, many researchers are working on repurposing existing drugs to alter the course of severe COVID-19, and are testing experimental treatments. Among antiviral agents, remdesivir, an RNA-dependent RNA polymerase inhibitor, showed clinical benefit in a randomized clinical trial. In October 2020, the Food and Drug Administration approved remdesivir for treating hospitalized patients with COVID-19, making it the first drug approved for the disease. The race to produce safe, effective vaccines is also progressing at unprecedented speed, with over 200 under development and 45 candidates already being tested in human clinical trials (as of October 2020).

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