scholarly journals Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase

2020 ◽  
Author(s):  
Jingyue Ju ◽  
Xiaoxu Li ◽  
Shiv Kumar ◽  
Steffen Jockusch ◽  
Minchen Chien ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Public Health Emergency ◽  
Molecular Structures ◽  
High Fidelity ◽  
Global Public Health ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Rna Dependent Rna Polymerase ◽  
Amino Acid Similarity ◽  
Nucleotide Analogues

SummarySARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.1 Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3’-fluoro-3’-deoxythymidine triphosphate and 3’-azido-3’-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

scholarly journals Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

2020 ◽  
Author(s):  
Minchen Chien ◽  
Thomas K. Anderson ◽  
Steffen Jockusch ◽  
Chuanjuan Tao ◽  
Shiv Kumar ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Molecular Basis ◽  
Molecular Structures ◽  
Rna Dependent Rna Polymerase ◽  
Nucleotide Analogues ◽  
Polymerase Inhibitors ◽  
Tenofovir Alafenamide ◽  
Potential Therapeutics ◽  
Tenofovir Diphosphate

AbstractSARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3’-fluoro-3’-deoxythymidine triphosphate, 3’-azido-3’-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.

scholarly journals Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp)

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7438
Author(s):  
Yifei Wu ◽  
David Crich ◽  
Scott D. Pegan ◽  
Lei Lou ◽  
Madelyn C. Hansen ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Reverse Transcriptase ◽  
Dna Polymerase ◽  
Binding Affinities ◽  
Hiv Reverse Transcriptase ◽  
Rna Dependent Rna Polymerase ◽  
Computational Approaches ◽  
Inhibitory Mechanisms ◽  
New Treatments ◽  
Potential Inhibitors

An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

scholarly journals Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Steffen Jockusch ◽  
Chuanjuan Tao ◽  
Xiaoxu Li ◽  
Minchen Chien ◽  
Shiv Kumar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dna Polymerase ◽  
Viral Genome ◽  
Molecular Basis ◽  
Molecular Structures ◽  
Genome Integrity ◽  
Brain Cells ◽  
High Fidelity

Abstract SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

scholarly journals Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

2020 ◽  
Author(s):  
Steffen Jockusch ◽  
Chuanjuan Tao ◽  
Xiaoxu Li ◽  
Minchen Chien ◽  
Shiv Kumar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dna Polymerase ◽  
Viral Genome ◽  
Molecular Basis ◽  
Molecular Structures ◽  
Genome Integrity ◽  
Brain Cells ◽  
High Fidelity

AbstractSARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2.1 We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase.2,3 Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells;4,5 additionally, COVID-19 clinical trials with EPCLUSA6 and with Sofosbuvir plus Daclatasvir7 have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity.8 Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

Life Lessons of the Pandemic ”Covid - 19”

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 469-471 ◽  
Author(s):  
Bhagyashri Vijay Chaudhari ◽  
Priya P. Chawle
Keyword(s):  
Public Health ◽  
Review Article ◽  
Public Health Emergency ◽  
The Novel ◽  
Global Public Health ◽  
Strange Situation ◽  
Republic Of China ◽  
Lifetime History ◽  
The People ◽  
Life Lessons

“A lesson learned the hard way is a lesson learned for a lifetime.” Every bad situation hurts; however, it sure does teach us something a lesson. In the same manner of a new lesson for Human lifetime, history is observing 'The Novel COVID-19 ’, a very horrible and strange situation created due to fighting with a microscopic enemy. WHO on 11 February 2020 has announced a name for new disease as - 19 and has declared as a global public health emergency and subsequently as pandemic because of its widespread. This began as an outbreak in December 2019, with its in Wuhan, the People Republic of China has emerged as a public health emergency of international concern. is the group of a virus with non-segmented, single-stranded and positive RNA genome. This bad situation of pandemic creates new scenes in the life of people in a different manner, which will be going to be life lessons for them. Such lessons should be kept in mind for the safety of living beings and many more things. In this narrative review article, reference was taken from a different article published in various databases which include the view of different authors and writers on the "Lessons to be from Corona".

scholarly journals Fullerene Derivatives of Nucleoside HIV Reverse Transcriptase Inhibitors—In Silico Activity Prediction

2018 ◽  
Vol 19 (10) ◽  
pp. 3231 ◽  
Author(s):  
Aleksandra Dąbrowska ◽  
Tomasz Pieńko ◽  
Przemysław Taciak ◽  
Katarzyna Wiktorska ◽  
Zdzisław Chilmonczyk ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Activity Prediction ◽  
Hiv Therapy ◽  
C20 Fullerene ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Similar Affinity ◽  
Hiv 1

Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The best of the designed compounds have superior or similar affinity to RT active site in comparison to most active test compounds, including drugs used in anti-HIV therapy.

scholarly journals The TREX2 3′→ 5′ Exonuclease Physically Interacts with DNA Polymerase δ and Increases Its Accuracy

2002 ◽  
Vol 2 ◽  
pp. 275-281 ◽  
Author(s):  
Igor V. Shevelev ◽  
Kristijan Ramadan ◽  
Ulrich Hubscher
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Error Rates ◽  
High Fidelity ◽  
Replication Machinery ◽  
Dna Polymerase Δ ◽  
Pol I ◽  
Calf Thymus ◽  
Mutation Assay ◽  
Forward Mutation

Proofreading function by the 3′→ 5′ exonuclease of DNA polymerase δ (pol δ) is consistent with the observation that deficiency of the associated exonuclease can lead to a strong mutation phenotype, high error rates during DNA replication, and ultimately cancer. We have isolated pol δdfrom isotonic (pol δi) and detergent (pol δd) calf thymus extracts. Pol δdhad a 20-fold higher ratio of exonuclease to DNA polymerase than pol δi. This was due to the physical association of the TREX2 exonuclease to pol δd, which was missing from pol δi. Pol δdwas fivefold more accurate than pol δiunder error-prone conditions (1 μM dGTP and 20 dATP, dCTP, and dTTP) in a M13mp2 DNA forward mutation assay, and fourfold more accurate in an M13mp2T90 reversion assay. Under error-free conditions (20 μM each of the four dNTPs), however, both polymerases showed equal fidelity. Our data suggested that autonomous 3′→ 5′ exonucleases, such as TREX2, through its association with pol I can guarantee high fidelity under difficult conditions in the cell (e.g., imbalance of dNTPs) and can add to the accuracy of the DNA replication machinery, thus preventing mutagenesis.

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