Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (413)

ProteinS (64)

NSP3 (57)

ComplexRdRp (51)

ProteinN (12)


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SARS-CoV-2 Proteins
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    Regulation of the Dimerization and Activity of SARS-CoV-2 Main Protease PROTEIN through Reversible Glutathionylation of Cysteine 300

    Authors: David A Davis; Haydar Bulut; Prabha Shrestha; Amulya Yaparla; Hannah K. Jaeger; Shin-ichiro Hattori; Paul Wingfield; Hiroaki Mitsuya; Robert Yarchoan

    doi:10.1101/2021.04.09.439169 Date: 2021-04-10 Source: bioRxiv

    SARS-CoV-2 encodes main protease PROTEIN ( Mpro PROTEIN), an attractive target for therapeutic interventions. We show Mpro PROTEIN is susceptible to glutathionylation leading to inhibition of dimerization and activity. Activity of glutathionylated Mpro PROTEIN could be restored with reducing agents or glutaredoxin HGNC. Analytical studies demonstrated that glutathionylated Mpro PROTEIN primarily exists as a monomer and that a single modification with glutathione is sufficient to block dimerization and loss of activity. Proteolytic digestions of Mpro PROTEIN revealed Cys300 as a primary target of glutathionylation, and experiments using a C300S Mpro PROTEIN mutant revealed that Cys300 is required for inhibition of activity upon Mpro PROTEIN glutathionylation. These findings indicate that Mpro PROTEIN dimerization and activity can be regulated through reversible glutathionylation of Cys300 and provides a novel target for the development of agents to block Mpro PROTEIN dimerization and activity. This feature of Mpro PROTEIN may have relevance to human disease and the pathophysiology of SARS-CoV-2 in bats, which develop oxidative stress during flight.

    Bead-assisted SARS-CoV-2 multi-antigen serological test allows effective identification of patients

    Authors: Yaiza Caceres-Martell; Daniel Fernandez-Soto; Carmen Campos-Silva; Eva Maria Garcia-Cuesta; Jose M. Casasnovas; David Navas-Herrera; Alexandra Beneitez-Martinez; Pedro Martinez-Fleta; Arantzazu Alfranca; Francisco Sanchez-Madrid; Gabriela Escudero-Lopez; Carlos Vilches; Ricardo Jara-Acevedo; Hugh T. Reyburn; Jose M. Rodriguez-Frade; Mar Vales-Gomez

    doi:10.1101/2021.04.08.21254348 Date: 2021-04-10 Source: medRxiv

    Many new aspects of COVID-19 MESHD disease, including different clinical manifestations, have been identified during the pandemic. The wide array of symptoms and variation in disease severity after SARS-CoV-2 infection MESHD might be related to heterogeneity in the immune responses of different patients. Here we describe a new method for a simple multi-antigen serological test that generates a full picture of seroconversion in a single reaction. The assay is based on the detection by flow cytometry of multiple immunoglobulin classes (isotypes) specific for four SARS-CoV-2 antigens: the Spike glycoprotein PROTEIN (one of the highly immunogenic proteins), its RBD fragment (the major target for neutralising antibodies), the nucleocapsid protein PROTEIN and the main cysteine-like protease PROTEIN. Until now, most diagnostic serological tests measured antibodies to only one antigen and some patients seemed to not make any antibody response. Our data reveal that while most patients respond against all the viral antigens tested, others show a marked bias to make antibodies against either proteins exposed on the viral particle or those released after cellular infection. Combining all the four antigens and using machine learning techniques, it was possible to clearly discriminate between patients and healthy controls with 100% confidence. Further, combination of antigens and different immunoglobulin isotypes in this multi-antigen assay improved the classification of patients with mild and severe disease. Introduction of this method will facilitate massive screenings of patients to evaluate their immune response. It could also support vaccination campaigns both to select non-immune individuals and to distinguish infected MESHD patients from vaccine responders.

    Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of nsp5 Main Protease PROTEIN

    Authors: Clovis Basier; Rupert Beale; Ganka Bineva-Todd; Berta Canal; Joseph F Curran; Tom D Deegan; John FX Diffley; Ryo Fujisawa; Michael Howell; Dhira Joshi; Karim Labib; Chew Theng Lim; Jennifer Milligan; Hema Nagaraj; George Papageorgiou; Christelle Soudy; Kang Wei Tan; Rachel Ulferts; Florian Weissmann; Mary Wu; Theresa U Zeisner

    doi:10.1101/2021.04.07.438806 Date: 2021-04-08 Source: bioRxiv

    The coronavirus 2019 ( COVID-19 MESHD) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5,000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.

    Structural dynamics of the β-coronavirus Mpro PROTEIN protease ligand binding sites

    Authors: Eunice Cho; Margarida Rosa; Ruhi Anjum; Saman Mehmood; Mariya Soban; Moniza Mujtaba; Khair Bux; Sarath Chandra Dantu; Alessandro Pandini; Junqi Yin; Heng Ma; Arvind Ramanathan; Barira Islam; Antonia Mey; DEBSINDHU BHOWMIK; Shozeb Haider

    doi:10.1101/2021.03.31.437918 Date: 2021-04-01 Source: bioRxiv

    {beta}-coronaviruses alone have been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a back-up against the emergence of lethal viral variants. One such target is the main protease PROTEIN ( Mpro PROTEIN) that plays an indispensible role in viral replication. The availability of over 270 Mpro PROTEIN X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV MESHD and MERS-CoV Mpro PROTEIN. Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across {beta}-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across {beta}-coronavirus homologs. This highlights the complexity in targeting all three Mpro PROTEIN enzymes with a single pan inhibitor.

    High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease PROTEIN Non-Covalent Inhibitor

    Authors: Austin Clyde; Stephanie Galanie; Daniel W. Kneller; Heng Ma; Yadu Babuji; Ben Blaiszik; Alexander Brace; Thomas Brettin; Kyle Chard; Ryan Chard; Leighton Coates; Ian Foster; Darin Hauner; Vilmos Kertesz; Neeraj Kumar; Hyungro Lee; Zhuozhao Li; Andre Merzky; Jurgen G. Schmidt; Li Tan; Mikhail Titov; Anda Trifan; Matteo Turilli; Hubertus Van Dam; Srinivas C. Chennubhotla; Shantenu Jha; Andrey Kovalevsky; Arvind Ramanathan; Marti Head; Rick Stevens

    doi:10.1101/2021.03.27.437323 Date: 2021-03-27 Source: bioRxiv

    Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel non-covalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease PROTEIN ( Mpro PROTEIN) by employing a scalable high throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro PROTEIN inhibitor with an inhibition constant (Ki) of 2.9 uM [95% CI 2.2, 4.0]. Further, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft MESHD in the primary binding site of Mpro PROTEIN forming stable hydrogen bond and hydrophobic interactions. We then used multiple s-timescale molecular dynamics ( MD MESHD) simulations, and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro PROTEIN, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro PROTEIN and offers a springboard for further therapeutic design.

    Inhibition Mechanism of SARS-CoV-2 Main Protease PROTEIN with Ketone-Based Inhibitors Unveiled by Multiscale Simulations

    Authors: Carlos A. Ramos-Guzmán; J. Javier Ruiz-Pernía; Iñaki Tuñón

    doi:10.26434/chemrxiv.13340939.v1 Date: 2021-03-26 Source: ChemRxiv

    We present the results of combined classical and QM/MM simulations for the inhibition of SARS-CoV-2 3CL protease PROTEIN by a recently proposed ketone-based covalent inhibitor, PF-00835231, that is under clinical trial. In the noncovalent complex formed after binding into the active site the carbonyl group of this inhibitor is accommodated into the oxyanion hole formed by the NH main chain groups of residues 143 to 145. The P1-P3 groups of the inhibitor establish similar interaction with the enzyme to those of equivalent groups in the natural peptide substrate, while the hydroxymethyl moiety of the inhibitor partly mimics the interactions established by the P1’ group of the peptide in the active site. Regarding the formation of the covalent complex, the reaction is initiated after the proton transfer from Cys145 to His41. Formation of the covalent hemithioacetal complex takes place by means of the nucleophilic attack of the Sg atom of Cys145 on the electron deficient carbonyl carbon atom and a proton transfer from the catalytic His41 to the carbonyl oxygen atom mediated by the hydroxyl group. Our findings can be used as a guide to propose modifications of the inhibitor in order to increase its affinity by the 3CL protease PROTEIN.

    Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

    Authors: Marie O. Pohl; Idoia Busnadiego; Francesco Marrafino; Lars Wiedmer; Annika Hunziker; Sonja Fernbach; Elena Omori; Benjamin G Hale; Amedeo Caflisch; Stertz Silke

    doi:10.1101/2021.03.19.435806 Date: 2021-03-19 Source: bioRxiv

    Rapid repurposing of existing drugs as new therapeutics for COVID-19 MESHD has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we screened by high-throughput docking 6,000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3CL main protease PROTEIN, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3CL main protease PROTEIN inhibitor in vitro (IC50 value of 29 M) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3CL main protease PROTEIN inhibitor in vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication in Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our study shows that combining computational and cellular screening is an efficient means to identify existing drugs with repurposing potential as antiviral compounds. Future studies should aim at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.

    SARS-CoV-2 Nsp5 HGNC Protein Causes Acute Lung Inflammation MESHD: A Dynamical Mathematical Model

    Authors: José Díaz; Elena R. Álvarez-Buylla; Antonio Bensussen

    id:10.20944/preprints202012.0749.v2 Date: 2021-03-15 Source: Preprints.org

    In the present work we propose a dynamical mathematical model of the lung cells inflammation process MESHD in response to SARS-CoV-2 infection MESHD. In this scenario the main protease PROTEIN Nsp5 HGNC enhances the inflammatory process, increasing the levels of NF kB, IL-6 HGNC, Cox2 HGNC, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 HGNC also increases above the threshold value of 7 pg mL-1 s-1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6 HGNC. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation MESHD state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5 HGNC.To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 HGNC is effectively a central node underlying the severe acute lung inflammation MESHD during SARS-CoV-2 infection MESHD. The persistent production of IL-6 HGNC by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19 MESHD. Nsp5 HGNC seems to be the switch to start inflammation MESHD, the consequent overproduction of the ACE2 HGNC receptor, and an important underlying cause of the most severe cases of COVID19 MESHD.

    Disulfiram associated with lower risk of Covid-19 MESHD: a retrospective cohort study

    Authors: Nathanael Fillmore; Steven Bell; Ciyue Shen; Vinh Nguyen; Jennifer La; Maureen Dubreuil; Judith Strymish; Mary Brophy; Gautam Mehta; Hao Wu; Judy Lieberman; Nhan Do; Chris Sander

    doi:10.1101/2021.03.10.21253331 Date: 2021-03-12 Source: medRxiv

    In the global COVID-19 pandemic MESHD, there is a substantial need for effective, low-cost therapeutics. We investigated the potential effects of disulfiram on the incidence and outcomes of COVID-19 MESHD in an observational study in a large database of US Veterans Administration clinical records, the VA Corporate Data Warehouse (CDW). The study is motivated by the unique properties of disulfiram, which has been used as an anti-alcoholism drug since 1948, is non-toxic, easy to manufacture and inexpensive. Disulfiram reduces hyperinflammation in mammalian cells by inhibition of the gasdermin D HGNC pore. In a mouse model of sepsis MESHD, disulfiram reduced inflammatory cytokines and mortality. Disulfiram also is a low micromolar inhibitor of the Mpro PROTEIN and PLpro PROTEIN viral proteases of SARS-CoV-2. To investigate the potential effects of disulfiram on the incidence and severity of COVID-19 MESHD, we carried out an epidemiological study in the CDW. The VA dataset used has 944,127 patients tested for SARS-Cov-2, 167,327 with a positive test, and 2,233 on disulfiram, of which 188 had a positive SARS-Cov-2 test. A multivariable Cox regression adjusted for age, gender, race/ethnicity, region, a diagnosis of alcohol use disorders, and Charlson comorbidity score revealed a reduced incidence of COVID-19 MESHD with disulfiram use with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). There were no deaths among the 188 SARS-Cov-2 positive patients treated with disulfiram. The expected number of deaths would have been 5-6 according to the 3% death rate among the untreated (P-value 0.03). Our finding of a lower hazard ratio and less severe outcomes for COVID-19 MESHD in patients treated with disulfiram compared to those not treated is a statistical association and does not prove any causative effect of disulfiram. However, the results of this study suggest that there is a pharmacological contribution to the reduced incidence and severity of COVID-19 MESHD with the use of disulfiram. Given the known anti-inflammatory and viral anti-protease effects of disulfiram, it is reasonable and urgent to initiate accelerated clinical trials to assess whether disulfiram reduces SARS-CoV-2 infection MESHD, disease severity and death MESHD.

    Novel inhibition mechanism of SARS-CoV-2 main protease PROTEIN by ebselen and its derivatives

    Authors: Kangsa Amporndanai; Xiaoli Meng; Haitao Yang; Zhie-Jie Liu; Leike Zhang; Yao Zhao; Samar Hasnain; Zihe Rao; Zhenming Jin; Weijuan Shang

    doi:10.1101/2021.03.11.434764 Date: 2021-03-11 Source: bioRxiv

    The global emergence of SARS-CoV-2 has triggered numerous efforts to develop therapeutic options for COVID-19 pandemic MESHD. The main protease PROTEIN of SARS-CoV-2 (Mpro PROTEIN), which is a critical enzyme for transcription and replication of SARS-CoV-2, is a key target for therapeutic development against COVID-19 MESHD. An organoselenium drug called ebselen has recently been demonstrated to have strong inhibition against Mpro PROTEIN and antiviral activity but its molecular mode of action is unknown preventing further development. We have examined the binding modes of ebselen and its derivative in Mpro PROTEIN via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro PROTEIN inhibition than ebselen and potent ability to rescue infected cells were observed for a number of ebselen derivatives. A free selenium atom bound with cysteine 145 of Mpro PROTEIN catalytic dyad has been revealed by crystallographic studies of Mpro PROTEIN with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct, formation of a phenolic by-product is confirmed by mass spectrometry. The target engagement of these compounds with an unprecedented mechanism of SARS-CoV-2 Mpro PROTEIN inhibition suggests wider therapeutic applications of organo-selenium compounds in SARS-CoV-2 and other zoonotic beta-corona viruses.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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