preVIEW: COVID-19

Corpus overview

Overview

MeSH Disease

RNA Virus Infections (14)

COVID-19 (9)

Hepatitis C (4)

Severe Acute Respiratory Syndrome (3)

Acquired Immunodeficiency Syndrome (2)


HGNC Genes

neurocan (1)


SARS-CoV-2 proteins

ComplexRdRp (14)

NSP12 (1)


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SARS-CoV-2 Proteins
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    Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex

    Authors: Brandon Malone; James Chen; Qi Wang; Eiiza Llewellyn; Young Joo Choi; Paul Dominic B. Olinares; Xinyun Cao; Carolina Hernandez; Edward T. Eng; Brian T. Chait; David E. Shaw; Robert Landick; Seth A. Darst; Elizabeth A. Campbell

    doi:10.1101/2021.03.13.435256 Date: 2021-03-14 Source: bioRxiv

    Backtracking, the reverse motion of the transcriptase enzyme on the nucleic acid template, is a universal regulatory feature of transcription in cellular organisms but its role in viruses is not established. Here we present evidence that backtracking extends into the viral realm, where backtracking by the SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) may aid viral transcription and replication. Structures of SARS-CoV-2 RdRp MESHD RdRp PROTEIN bound to the essential nsp13 helicase and RNA suggested the helicase facilitates backtracking. We use cryo-electron microscopy, RNA-protein crosslinking, and unbiased molecular dynamics simulations to characterize SARS-CoV-2 RdRp MESHD RdRp PROTEIN backtracking. The results establish that the single-stranded 3'-segment of the product-RNA generated by backtracking extrudes through the RdRp PROTEIN NTP-entry tunnel, that a mismatched nucleotide at the product-RNA 3'-end frays and enters the NTP-entry tunnel to initiate backtracking, and that nsp13 stimulates RdRp PROTEIN backtracking. Backtracking may aid proofreading, a crucial process for SARS-CoV-2 resistance against antivirals.

    In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp MESHD RdRp PROTEIN

    Authors: Khushboo Pandey; Kiran Bharat Lokhande; K. venkateswara Swamy; Shuchi Nagar; Manjusha Dake

    doi:10.21203/rs.3.rs-225174/v1 Date: 2021-02-09 Source: ResearchSquare

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp PROTEIN of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp MESHD RdRp PROTEIN, they were subjected to molecular docking, 100ns molecular dynamics ( MD MESHD) simulation followed by post-simulation analysis. Further, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp PROTEIN revealed that, EBDGp possess stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity towards SARS-CoV-2 RdRp MESHD RdRp PROTEIN. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp MESHD RdRp PROTEIN. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp PROTEIN-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

    Lost in translation: codon optimization inactivates SARS-CoV-2 RdRp PROTEIN

    Authors: Bing Wang; Vladimir Svetlov; Evgeny Nudler; Irina Artsimovitch

    doi:10.1101/2021.01.24.428004 Date: 2021-01-25 Source: bioRxiv

    RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) is a primary target for antivirals. We report that Nsp12, a catalytic subunit of SARS-CoV-2 RdRp MESHD RdRp PROTEIN, produces an inactive enzyme when codon-optimized for bacterial expression. We also show that accessory subunits, NTPs, and translation by slow ribosomes partially rescue Nsp12. Our findings have implications for functional studies and identification of novel inhibitors of RdRp PROTEIN and for rational design of other biotechnologically and medically important expression systems.

    Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19 MESHD

    Authors: H. Eric Xu; Wanchao Yin; Xiaodong Luan; Zhihai Li; Leike Zhang; Ziwei Zhou; Minqi Gao; Xiaoxi Wang; Zhou Fulai; Jingjing Shi; Erli You; Mingliang Liu; Qingxia Wang; Qingxing Wang; Yi Jiang; Hualiang Jiang; Gengfu Xiao; Xuekui Yu; Shuyang Zhang

    doi:10.21203/rs.3.rs-99513/v1 Date: 2020-10-28 Source: ResearchSquare

    The COVID-19 MESHD COVID-19 MESHD pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19 MESHD. The 2.6 Å cryo-EM structure of the viral RdRp PROTEIN bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp PROTEIN catalytic active site. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp MESHD RdRp PROTEIN and a rationale for repurposing suramin for treating COVID-19 MESHD.

    Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19 MESHD

    Authors: Wanchao Yin; Xiaodong Luan; Zhihai Li; Leike Zhang; Ziwei Zhou; Minqi Gao; Xiaoxi Wang; Fulai Zhou; Jingjing Shi; Erli You; Mingliang Liu; Qingxia Wang; Qingxing Wang; Yi Jiang; Hualiang Jiang; Gengfu Xiao; Xuekui Yu; Shuyang Zhang; Sandra Lawrynowicz Leibel; Oren Zimhony; Aaron F. Carlin; Gur Yaari; Moshe Dassau; Meital Gal-Tanamy; David Hagin; Ben A. Croker; Natalia Freund; Huijuan Yang; Shan Lu; Xuanyi Wang; Yang Gao; Xingli Xu; Linrui Cai; Jian Zhou; Li Yu; Zhuo Chen; Chao Hong; Dan Du; Hongling Zhao; Yan Li; Kaili Ma; Yunfei Ma; Donglan Liu; Shibao Yao; Changgui Li; Yanchun Che; Longding Liu; Qihan Li

    doi:10.1101/2020.10.06.328336 Date: 2020-10-06 Source: bioRxiv

    The COVID-19 MESHD COVID-19 MESHD pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19 MESHD. The 2.6 [A] cryo-EM structure of the viral RdRp PROTEIN bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp PROTEIN catalytic active site, therefore inhibiting the viral RNA replication. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp MESHD RdRp PROTEIN and a rationale for repurposing suramin for treating COVID-19 MESHD.

    Development of a simple in vitro assay to identify and evaluate nucleotide analogs against SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN

    Authors: Gaofei Lu; Xi Zhang; Weinan Zheng; Jialei Sun; Lan Hua; Lan Xu; Xin-jie Chu; Sheng Ding; Wen Xiong

    doi:10.1101/2020.07.16.205799 Date: 2020-07-17 Source: bioRxiv

    Nucleotide analogs targeting viral RNA polymerase have been approved to be an effective strategy for antiviral treatment and are attracting antiviral drugs to combat the current SARS-CoV-2 pandemic. In this report, we develop a robust in vitro nonradioactive primer extension assay to evaluate the incorporation efficiency of nucleotide analog by SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) quantitively. Our results show that many nucleotide analogs can be incorporated into RNA by SARS-CoV-2 RdRp MESHD RdRp PROTEIN, and that the incorporation of some of them leads to chain termination. The discrimination values of nucleotide analog over those of natural nucleotide were measured to evaluate the incorporation efficiency of nucleotide analog by RdRp PROTEIN. We found that the incorporation efficiency of Remdesivir-TP is higher than ATP, and we did not observe chain termination or delayed chain termination caused by single Remdesivir-TP incorporation, while multiple incorporations of Remdesivir-TP caused chain termination in our assay condition. The incorporation efficiency of Ribavirin-TP and Favipiravir-TP is very low either as ATP or GTP analogs, which suggested that mutagenesis may not be the mechanism of action of those two drugs against SARS-CoV-2. Incorporation of Sofosbuvir-TP is also very low suggesting that sofosbuvir may not be very effective in treating SARS-CoV-2 infection MESHD. As a comparison, 2-C-Methyl-GTP can be incorporated into RNA efficiently, and the derivative of 2-C-Methyl-GTP may have therapeutic application in treating SARS-CoV-2 infection MESHD. This report provides a simple screening method that should be useful in evaluating nucleotide-based drugs targeting SARS-CoV-2 RdRp PROTEIN, and for studying the mechanism of action of selected nucleotide analog.

    Foundational research and NIH funding enabling Emergency Use Authorization of remdesivir for COVID-19 MESHD

    Authors: Ekaterina Galkina Cleary; Matthew J. Jackson; Zoe Folchman-Wagner; Fred D. Ledley

    doi:10.1101/2020.07.01.20144576 Date: 2020-07-06 Source: medRxiv

    Emergency Use Authorization for remdesivir months after discovery of COVID19 MESHD is unprecedented. Typically, decades of research and public sector funding are required to establish the mature body of foundational research requisite for efficient, targeted drug discovery and development. This work quantifies the body of research related to the biological target of remdesivir, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN), or parent chemical structure, nucleoside analogs ( NcAn HGNC), through 2019, as well as NIH funding for this research from 2000 to 2019. There were 6,567 RdRp PROTEIN related publications in PubMed, including 1,263 with NIH support, and 11,073 NcAn HGNC-related publications, including 2,319 with NIH support. NIH support for RdRp PROTEIN research comprised 2,203 Project Years with Costs of $1,875 million. NIH support for NcAn HGNC research comprised 4,607 Project Years with Costs of $4,612 million. Research Project grants accounted for 63% and 48% of Project Years for RdRp MESHD RdRp PROTEIN and NcAn HGNC respectively, but only 19% and 12% of Project Costs. Analytical modeling of research maturation estimates that RdRp PROTEIN and NcAn HGNC research passed an established maturity threshold in 2008 and 1994 respectively. Of 97 investigational compounds targeting RdRp PROTEIN since 1989, the three authorized for use entered clinical trials after both thresholds. This work demonstrates the scale of foundational research on the biological target and parent chemical structure of remdesivir that supported its discovery and development for COVID19 MESHD. This work identifies $6.5 billion in NIH funding for research leading to remdesivir, underscoring the role of public sector investments in basic research and research infrastructure that underlie new drugs and the response to emergent disease MESHD.

    Predicting inhibitors for SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN using machine learning and virtual screening

    Authors: Romeo Cozac; Nazim Medzhidov; Shinya Yuki

    id:2006.06523v1 Date: 2020-06-09 Source: arXiv

    Global coronavirus disease MESHD pandemic ( COVID-19 MESHD) caused by newly identified SARS- CoV-2 coronavirus continues to claim the lives of thousands of people worldwide. The unavailability of specific medications to treat COVID-19 MESHD has led to drug repositioning efforts using various approaches, including computational analyses. Such analyses mostly rely on molecular docking and require the 3D structure of the target protein to be available. In this study, we utilized a set of machine learning algorithms MESHD and trained them on a dataset of RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) inhibitors to run inference analyses on antiviral and anti-inflammatory drugs solely based on the ligand information. We also performed virtual screening analysis of the drug candidates predicted by machine learning models and docked them against the active site of SARS- CoV-2 RdRp PROTEIN, a key component of the virus replication machinery. Based on the ligand information of RdRp PROTEIN inhibitors, the machine learning models were able to identify candidates such as remdesivir and baloxavir marboxil, molecules with documented activity against RdRp PROTEIN of the novel coronavirus. Among the other identified drug candidates were beclabuvir, a non-nucleoside inhibitor of the hepatitis C virus MESHD ( HCV MESHD) RdRp PROTEIN enzyme, and HCV MESHD protease inhibitors paritaprevir and faldaprevir. Further analysis of these candidates using molecular docking against the SARS-CoV-2 RdRp PROTEIN revealed low binding energies against the enzyme active site. Our approach also identified anti-inflammatory drugs lupeol, lifitegrast, antrafenine, betulinic acid, and ursolic acid to have potential activity against SARS-CoV-2 RdRp MESHD RdRp PROTEIN. We propose that the results of this study are considered for further validation as potential therapeutic options against COVID-19 MESHD.

    Understanding the Origin of ‘BatCoVRaTG13’, a Virus Closest to SARS-CoV-2

    Authors: Monali C. Rahalkar; Rahul A. Bahulikar

    id:202005.0322/v2 Date: 2020-05-24 Source: Preprints.org

    Genomic analysis indicates that SARS-CoV-2 is most related to RaTG13, a beta corona virus derived from bats by 96% 1. At present, RaTG13 is only available on the public database in the form of a genome sequence. The genome of RaTG13 (MN996532.1) was sequenced from the RNA of a bat faecal swab collected in 2013 from Yunnan, China, however the exact location is not mentioned. Since RaTG13 is one of the main supports for SARS-CoV-2 to have a natural origin, it is of utmost importance to understand the sample location. RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) sequence of RaTG13 shows that it is 100% similar to that of bat corona virus BtCoV/4991 and 98.7-98.9% similar to SARS-CoV-2 RdRp MESHD RdRp PROTEIN 2. BtCoV/4991 was described to be a SARS-like (SL-) corona virus from bat faeces sampled in an abandoned mine from Mojiang 2. Both the publications 1,2 are authored by Dr. Zheng-li Shi (Z-L Shi), who is described as the bat woman of China 3. However, BtCoV/4991 has not been mentioned by Zhou et al 2020 1 where novel corona virus was first described. Based on the RdRp PROTEIN sequence similarities, similarities in sample collection dates, sample locations, and the fact that RaTG13 is mentioned synonymous to BtCoV/4991 on the Chinese bat database, it is predicted that RaTG13 and BtCoV/4991 originate from the same sample. The sample, bat faecal swab was collected in 2013 from an abandoned mineshaft in Mojiang by Dr. Shi and her work group. In 2012, in a Mojiang mineshaft, six mine workers suffered from atypical pneumonia MESHD and three of them died. These workers were engaged in the work of clearing debris from a mineshaft which had a lot of bats and bat faeces 3,4. A detailed health investigation indicated that the miners suffered from atypical pneumonia MESHD mostly of the viral origin 4. Therefore, in the light of the present Covid-19 MESHD caused by SARS-CoV-2, the fact that its phylogenetic neighbour RaTG13 originated from bat faeces collected from a mineshaft, which was also the origin of pneumonia-like disease MESHD in miners in 2012, should be noted.

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

    Authors: Kunal Dutta; Sergey Shityakov; Olga Morozova; Ibrahim Khalifa; Jin Zhang; Wei Zhu; Amiya Panda

    id:10.20944/preprints202003.0395.v2 Date: 2020-04-02 Source: Preprints.org

    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 MESHD patients are unknown. In this present initiative, molecular interactions between FDA-approved antiviral drugs against the Hepatitis-C virus MESHD ( HCV MESHD) have been investigated theoretically against the RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) of SARS-CoV-2. HCV MESHD 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 MESHD RdRp SARS-CoV-2 PROTEIN (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.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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