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    Protein-primed RNA synthesis in SARS-CoVs MESHD and structural basis for inhibition by AT-527

    Authors: Ashleigh Shannon; Veronique Fattorini; Bhawna Sama; Barbara Selisko; Mikael Feracci; Camille Falcou; Pierre Gauffre; Priscila El Kazzi; Etienne Decroly; Nadia Rabah; Karine Toulon; Cecilia Eydoux; Jean-Claude Guillemot; Mathieu Noel; Francoise Debart; Jean-Jacques Vasseur; Adel Moussa; Steven Good; Kai Lin; Jean-Pierre Sommadossi; Yingxiao Zhu; Xiaodong Yan; Hui Shi; Francois Ferron; Bruno Canard

    doi:10.1101/2021.03.23.436564 Date: 2021-03-23 Source: bioRxiv

    How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and -2 Nidovirus RdRp PROTEIN-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP- Nsp HGNC8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp PROTEIN active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA synthesis at the precise genome-poly(A) junction. The guanosine analogue 5'-triphosphate AT-9010 (prodrug: AT-527) tightly binds to the NiRAN and inhibits both nsp8-labeling and the initiation of RNA synthesis. A 2.98 A resolution Cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 /RNA/NTP quaternary complex shows AT-9010 simultaneously binds to both NiRAN and RdRp PROTEIN active site of nsp12, blocking their respective activities. AT-527 is currently in phase II clinical trials, and is a potent inhibitor of SARS-CoV-1 and -2, representing a promising drug for COVID-19 MESHD treatment.

    Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV- 2 Non-Structural Proteins PROTEIN Implicated in Viral Pathogenesis

    Authors: Von Novi de Leon; Joe Anthony Manzano; Delfin Yñigo H. Pilapil; Rey Arturo T. Fernandez; James Kyle Ching; Mark Tristan J. Quimque; Kin Israel Notarte; Allan Patrick Macabeo

    doi:10.26434/chemrxiv.14125433.v1 Date: 2021-03-01 Source: ChemRxiv

    Background: Accessing COVID-19 MESHD vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 MESHD treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV- 2 non-structural proteins PROTEIN (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity MESHD. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease PROTEIN ( nsp3 HGNC), 3-chymotrypsin-like protease ( nsp5 HGNC), RNA-dependent RNA polymerase PROTEIN (nsp12), helicase HGNC (nsp13), SAM-dependent 2’-O-methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness MESHD and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity MESHD was also determined using OSIRIS Property Explorer. Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (1), robustaflavone (4), punicalin (9), volkensiflavone (11), rhusflavanone (13), morelloflavone (14), hinokiflavone (15), and michellamine B (19) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (2), pomolic acid (5), ursolic acid (10), garcisaterpenes A (12), hinokiflavone (15), and digitoxigenin-3-O-glucoside (17) were computationally druggable. Moreover, compounds 5 and 17 showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic. Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3 HGNC, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti- COVID-19 MESHD drug design.

    Unravelling Vitamins as Wonder Molecules for Covid-19 MESHD Management via Structure-based Virtual Screening

    Authors: Medha Pandya; Sejal Shah; Dhanalakshmi Menamadathil; Ayushman Gadnayak; Tanzil Juneja; Amisha Patel; Kajari Das; Jayashankar Das

    doi:10.21203/rs.3.rs-144177/v1 Date: 2021-01-09 Source: ResearchSquare

    The emergence situation of coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic has realised the global scientific communities to develop strategies for immediate priorities and long-term approaches for utilization of existing knowledge and resources which can be diverted to pandemic preparedness planning. Lack of proper vaccine candidate and therapeutic management has accelerated the researchers to repurpose the existing drugs with known preclinical and toxicity MESHD profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. We focused to justify even exploration of supplements, nutrients and vitamins to dampen the disease burden of the current pandemic may play a crucial role for its management. We have explored structure based virtual screening of 15 vitamins against non-structural ( NSP3 HGNC NSP3 PROTEIN, NSP5 PROTEIN NSP5 HGNC, ORF7a PROTEIN, NSP12 PROTEIN, ORF3a PROTEIN), structural (Spike & Hemagglutinin esterase) and host protein furin HGNC. The in silico analysis exhibited that vitamin B12, Vitamin B9, Vitamin D3 determined suitable binding while vitamin B15 manifested remarkable H-bond interactions with all targets. Vitamin B12 bestowed the lowest energies with human furin HGNC and SARS-COV-2 RNA dependent RNA polymerase PROTEIN. Furin HGNC mediated cleavage of the viral spike glycoprotein PROTEIN is directly related to enhanced virulence of SARS-CoV-2. In contrast to these, vitamin B12 showed zero affinity with SARS-CoV-2 spike PROTEIN protein. These upshots intimate that Vitamin B12 could be the wonder molecule to shrink the virulence by hindering the furin HGNC mediated entry of spike to host cell. These identified molecules may effectively assist in SARS-CoV-2 therapeutic management to boost the immunity by inhibiting the virus imparting relief in lung inflammation MESHD.

    Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV- 2 non-structural proteins PROTEIN

    Authors: Igors Dubanevics; Charles Heaton; Carlos Riechmann; Tom C B McLeish; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.12.422477 Date: 2020-12-14 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic MESHD, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro PROTEIN ( nsp5 HGNC) to three other SARS-CoV-2 proteins: host shutoff factor PROTEIN ( nsp1 HGNC), papain-like protease PROTEIN ( nsp3 HGNC, also known as PLpro PROTEIN) and RNA-dependent RNA-polymerase PROTEIN (nsp12, also known as RdRp) in complex PROTEIN with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

    An in silico approach to target SARS-CoV-2 RNA dependent RNA polymerase PROTEIN of COVID-19 MESHD with naturally occurring phytochemicals

    Authors: Hafiza Salaha Mahrosh; Ghulam Mustafa

    doi:10.21203/rs.3.rs-107572/v2 Date: 2020-11-13 Source: ResearchSquare

    The novel coronavirus disease 2019 MESHD ( COVID-19 MESHD) was firstly reported from Wuhan city of China found as highly contagious, transmittable and pathogenic viral infection MESHD. The World Health Organization declared COVID-19 MESHD as a pandemic since its emergence from China. The RNA dependent RNA polymerase PROTEIN ( nsp HGNC-12) is a complex with nsp HGNC-7 and nsp HGNC-8 cofactors major constituent of viral replication and RNA synthesis machinery. In current study, the RdRp PROTEIN of virus was selected as a receptor protein for computational drug discovery. Computational homology modelling was done in order to find the hidden secondary structures and structural assessment of viral protein to target them via antiviral drugs. The study based on docking of different phytochemicals to check potential of different plant metabolites against viral replicative proteins. Out of 200 ligands used in this study from different plants the best ten were selected based on drug discovery parameters such as S-score, ligand interactions, hydrophobic interactions and drug likeness. The ten best selected ligands were Verbenalin, Epigallocatechin, Swertisin, Nobiletin, Pinoresinol, Caftaric acid, Hesperetin, Islandicin, Neochlorogenic acid and Sesamin that exploit the potency as antagonist of viral protein. Among binding interactions of all ligands Arg339 centred as the main interacting residue among almost all the ligands. Till now many antiviral agents have shown potency in only mild cases of SARS-CoV-2 but no effective drug has been found for critical pulmonary cases. In clinical trials many broad-spectrum antiviral agents have been still in trail periods of testing against SARS-CoV-2. Till date no effective drug or vaccine has been validated with significant efficacy and potency against the SARS-CoV-2 therefore there is an urgent need to design effective vaccine against nCoV-19 infections. 

    Drug Design and Repurposing with DockThor-VS Web Server: Virtual Screening focusing on SARS-CoV-2 Therapeutic Targets and their Non-Synonym Variants

    Authors: Isabella A. Guedes; Leon S. C. Costa; Karina B. dos Santos; Ana L. M. Karl; Gregório K. Rocha; Iury M. Teixeira; Marcelo M. Galheigo; Vivian Medeiros; Eduardo Krempser; Fábio L. Custódio; Helio J. C. Barbosa; Marisa F. Nicolás; Laurent E. Dardenne

    doi:10.21203/rs.3.rs-96789/v1 Date: 2020-10-22 Source: ResearchSquare

    The COVID-19 MESHD caused by the SARS-CoV-2 virus was declared as a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. Currently, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 HGNC (papain-like, PLpro PROTEIN domain), Nsp5 HGNC ( Mpro PROTEIN, 3CLpro PROTEIN), Nsp12 ( RdRp PROTEIN), Nsp15 (NendoU), N protein PROTEIN and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations in the identification of possible new treatments of SARS-CoV-2 infections MESHD. The DockThor-VS is freely available at www.dockthor.lncc.br.

    Hallmarks of Alpha- and Betacoronavirus non-structural protein 7 PROTEIN+8 complexes

    Authors: Boris Krichel; Ganesh Bylapudi; Christina Schmidt; Clement Blanchet; Robin Schubert; Lea Brings; Martin Koehler; Renato Zenobi; Dmitri Svergun; Kristina Lorenzen; Ramakanth Madhugiri; John Ziebuhr; Charlotte Uetrecht

    doi:10.1101/2020.09.30.320762 Date: 2020-09-30 Source: bioRxiv

    Coronaviruses infect MESHD many different species including humans. The last two decades have seen three zoonotic coronaviruses with SARS-CoV-2 causing a pandemic in 2020. Coronaviral non-structural proteins ( nsp HGNC) built up the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate the RNA-dependent RNA-polymerase PROTEIN and other enzymes in the RTC. However, the structural plasticity of nsp7+8 complex has been under debate. Here, we present the framework of nsp7+8 complex stoichiometry and topology based on a native mass spectrometry and complementary biophysical techniques of nsp7+8 complexes from seven coronaviruses in the genera Alpha- and Betacoronavirus including SARS-CoV-2. Their complexes cluster into three groups, which systematically form either heterotrimers or heterotetramers or both, exhibiting distinct topologies. Moreover, even at high protein concentrations mainly heterotetramers are observed for SARS-CoV-2 nsp7+8. From these results, the different assembly paths can be pinpointed to specific residues and an assembly model is proposed.

    Attacking the SARS-CoV-2 Replication Machinery with the Pathogen Box’s Molecules

    Authors: Cleidy Osorio-Mogollon; Gustavo E. Olivos-Ramirez; Kewin Otazu; Manuel E. Chenet-Zuta; Georcki Ropon-Palacios; Ihosvany Camps; Gabriel M. Jimenez-Avalo; Eduardo Apari-Cossio; Natalia E. Torres-Moreira; Reyna G. Cardenas-Cardenas

    doi:10.26434/chemrxiv.12501791.v1 Date: 2020-06-19 Source: ChemRxiv

    The world is currently facing a pandemic caused by the new 2019 coronavirus disease MESHD ( COVID-19 MESHD), caused by SARS-CoV-2. Among the fundamental processes of this virus are viral transcription and replication. They allow the synthesisof genetic material and the consequent multiplication of the virus to infect other cells or organisms. These are performed by a multi-subunit machinery of various nonstructural proteins ( nsp HGNC); among which the RNA-dependent RNApolymerase ( RdRp PROTEIN or nsp12) is the most important, and, at the same time, conserved among coronaviruses. The structure of this protein (PDB ID: 6M71) was used as a target in the application of computational strategies for drugsearch, like virtual screening and molecular docking. The region considered for virtual screening has three important amino acids for protein catalysis: T680 (located in Motif A), N691 and D623 (located in Motif B), where a grid box was located. In turn, applying the concept of drug repositioning isconsidered as a quick response in the treatment of sudden outbreaks of diseases. Here, we used the Pathogen Box, a database of chemical compounds analyzed for the treatment against malaria MESHD, which were filtered under the criteria of selecting those that do not present any violation of Lipinski'sRule of Five. At the same time, the Remdesivir, Beclabuvir and Sofosbuvir drug, previously used in in silico and clinical studies for inhibition of nsp12, were used as positive controls. The results showed a Top10 potential target inhibitors, with binding energy higher than those of the positive controls, of which TCMDC-134153 and TCMDC-135052, both with -7.53 kcal/mol, present interactions with the three important residues of the nsp12 catalytic site. These proposed ligands would be used for subsequent validation by molecular dynamics, where they can beconsidered as drugs for the development of effective treatments against this new pandemic.

    Identification of best suitable repurposed drugs considering mutational spectra at RdRp PROTEIN (nsp12), 3CLpro PROTEIN ( nsp 5 HGNC) and PLpro PROTEIN ( nsp 3 HGNC) of SARS-CoV-2 in Indian population

    Authors: Shuvam Banerjee; Riju Dey; Sohan Seal; Kousik Kr. Mondal; Pritha Bhattacharjee

    doi:10.21203/rs.3.rs-33879/v1 Date: 2020-06-05 Source: ResearchSquare

    Background and Objective: COVID-19 MESHD originated in Wuhan, China and expanded to different geographical location of the world with variation in its sequence due to mutation, consequent alteration in different protein structures; resulting in different interaction with the host body. The highly infectious and diverge character of the virus makes it imperative to identify the promising inhibitory compounds for RdRp PROTEIN, 3CLpro PROTEIN and PLpro PROTEIN as suitable antiviral drug target so that viral duplication can be prevented in the host body.Methods: RdRp PROTEIN, 3CLpro PROTEIN and PLpro PROTEIN sequences of Indian patients were retrieved from the database and MSA was employed to identify mutation at nsp 3 HGNC, nsp 5 HGNC and nsp 12. Protein structures were modeled considering all possible combination of sequences abundant in India and docking was performed with repurposed drugs, currently under trial for COVID-19 MESHD, using Autodock Vina to find out the suitable ones considering the mutational spectra of SARS-CoV-2 in India.Results: PLpro PROTEIN is found to be most vulnerable to mutations with four mutations found in >5% studied population whereas in 3CLpro PROTEIN none observed at the frequency > 5%, so far. Two mutations were reported among Indian population (>5%) at RdRp PROTEIN. Therefore 3CLpro PROTEIN and RdRp PROTEIN were further analysed as a suitable target for repurposed drugs. Elbasvir has come up as the most suitable drug to inhibit the activity of RdRp PROTEIN in Indian population, followed by Remdesivir and Methylprednisolone. TMC 310911, Lopinavir and Elbasvir again, found to be the best candidates for inhibiting 3CLpro PROTEIN.Interpretation and Conclusions: Remdesivir and Lopinavir(alone or in combination with Ritonavir), the most popular drugs of choice at recent times may be suitable to be used in Indian population, considering the mutational variations in Indian population. Among others, Elbasvir, TMC 310911 and Methylprednisolone are good choices for treating COVID-19 MESHD.

    Computational Drug Repurposing Studies on SARS-CoV-2 Protein Targets

    Authors: Guangfeng Zhou; Lance Stewart; Gabriella Reggiano; Frank DiMaio

    doi:10.26434/chemrxiv.12315437.v1 Date: 2020-05-18 Source: ChemRxiv

    To contribute to the combat of COVID-2019, we applied structure-based computational docking screens using flexible docking protocol of Rosetta GALigandDock against multiple potential SARS-CoV-2 protein targets, including the Nsp5 HGNC 3-chymotrypsin-like protease ( 3CLpro PROTEIN), the Nsp3 ADP ribose phosphatase, the Nsp15 Endoribonuclease, the RNA binding domain of nucleocapsid phosphoprotein, the Nsp16 2'-O-MTase, Nsp14, and Nsp12 RNA-dependent RNA polymerase PROTEIN. Screening against a re-purposing library of 8,395 FDA approved drugs at various stages of drug development and various natural products from DrugBank, we found a total of 124 putative inhibitors with predicted binding ∆G less than -8.9 kcal/mol, including HIV-AIDS MESHD drugs Nelfinavir and Tipranavir, targeting 3Clpro with ∆G=-18.8 kcal/mol and ∆G=-16.6 kcal/mol respectively. These primarily involve binders to the Nsp5 HGNC 3CLpro PROTEIN (37 hits) and the Nsp3 ADP ribose phosphatase (36 hits), with smaller numbers of hits to other targets. These small molecule putative inhibitors suggest a possible avenue for drug repurposing, and the identified compounds should serve as a high-priority list for experimental validation via co-crystallization, enzymatic and cell based assays.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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