Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (412)

ProteinS (63)

NSP3 (57)

ComplexRdRp (51)

ProteinN (11)


SARS-CoV-2 Proteins
    displaying 41 - 50 records in total 412
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    Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

    Authors: Anneliese Ashhurst; Arthur Tang; Pavla Fajtova; Michael Yoon; Anupriya Aggarwal; Alexander Stoye; Mark Larance; Laura Beretta; Aleksandra Drelich; Danielle Skinner; Linfeng Li; Thomas Meek; James McKerrow; Vivian Hook; Chien-Te Tseng; Stuart Grant Turville; William Gerwick; Richard J Payne; Myra Hosmillo; Malte L Pinckert; Iliana Georgana; Anna Yakovleva; Laura G Caller; Sarah L Caddy; Theresa Feltwell; Fahad A Khokhar; Charlotte J Houldcroft; Martin D Curran; Surendra Parmar; - The COVID-19 Genomics UK (COG-UK) Consortium; Alex Alderton; Rachel Nelson; Ewan Harrison; John Sillitoe; Stephen D Bentley; Jeffrey C Barrett; M. Estee Torok; Ian G Goodfellow; Cordelia Langford; Dominic Kwiatkowski; - Wellcome Sanger Institute COVID-19 Surveillance Team

    doi:10.1101/2020.12.23.424111 Date: 2020-12-25 Source: bioRxiv

    The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic MESHD COVID-19 pandemic MESHD, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L HGNC is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L HGNC activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B HGNC and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro PROTEIN and PLpro PROTEIN. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection MESHD in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L HGNC as a COVID-19 MESHD antiviral drug target.

    Dimer-monomer equilibrium of SARS-CoV-2 main protease PROTEIN as affected by small molecule inhibitors: a biophysical investigation

    Authors: Lucia Silvestrini; Norhan Belhaj; Lucia Comez; Yuri Gerelli; Antonino Lauria; Valeria Libera; Paolo Mariani; Paola Marzullo; Maria Ortore; Antonio Palumbo Piccionello; Caterina Petrillo; Lucrezia Savini; Alessandro Paciaroni; Francesco Spinozzi

    doi:10.21203/ Date: 2020-12-24 Source: ResearchSquare

    The maturation of coronavirus SARS-CoV-2 MESHD, which is the etiological agent at the origin of the COVID-19 pandemic MESHD, requires a main protease PROTEIN Mpro PROTEIN to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro PROTEIN monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro PROTEIN is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit small angle x-ray scattering ( SAXS MESHD) to investigate the structural features of the SARS-CoV-2 Mpro PROTEIN monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS MESHD is also used to study how the Mpro PROTEIN dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro PROTEIN dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro PROTEIN functionality.

    A Crystallographic Snapshot of SARS-CoV-2 Main Protease PROTEIN Maturation Process

    Authors: Gabriela Noske; Aline Nakamura; Victor Gawriljuk; Rafaela Fernandes; Gustavo Lima; Higor Rosa; Humberto Pereira; Ana Zeri; Andrey Nascimento; Marjorie Freire; Glaucius Oliva; Andre Schutzer de Godoy; Jan Postberg

    doi:10.1101/2020.12.23.424149 Date: 2020-12-23 Source: bioRxiv

    SARS-CoV-2 is the causative agent of COVID-19 MESHD. The dimeric form of the viral main protease PROTEIN is responsible for the cleavage of the viral polyprotein in 11 sites, including its own N and C-terminus. Herein, we used X-ray crystallography to characterize an immature form of the main protease PROTEIN. We propose that this form preludes the cis-cleavage of N-terminal residues within the dimer, leading to the mature active site. Using fragment screening, we probe new cavities in this form which can be used to guide therapeutic development. Furthermore, we characterized a serine site-directed mutant of the main protease PROTEIN bound to its endogenous N and C-terminal residues during the formation of the tetramer. This quaternary form is also present in solution, suggesting a transitional state during the C-terminal trans-cleavage.

    An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease PROTEIN inhibitors with in vitro antiviral activity

    Authors: Naoya Kitamura; Michael Dominic Sacco; Chunlong Ma; Yanmei Hu; Julia Townsend; Xiangzhi Meng; Fushun Zhang; Xiujun Zhang; Adis Kukuljac; Michael Marty; David Schultz; Sara Cherry; Yan Xiang; Yu Chen; Jun Wang

    doi:10.1101/2020.12.19.423537 Date: 2020-12-20 Source: bioRxiv

    The main protease PROTEIN ( Mpro) of SARS-CoV-2 PROTEIN is a validated antiviral drug target. Several Mpro PROTEIN inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II and XII, each containing a reactive warhead that covalently modifies the catalytic Cys145. In this study, we report an expedited drug discovery approach by coupling structure-based design and Ugi four-component (Ugi-4CR) reaction methodology to the design of non-covalent Mpro PROTEIN inhibitors. The most potent compound 23R had cellular antiviral activity similar to covalent inhibitors such as GC376. Our designs were guided by overlaying the structure of SARS-CoV MESHD Mpro PROTEIN + ML188 (R), a non-covalent inhibitor derived from Ug-4CR, with the X-ray crystal structures of SARS-CoV-2 Mpro PROTEIN + calpain inhibitor XII/GC376/UAWJ247. Binding site analysis suggests a strategy of extending the P2 and P3 substitutions in ML188 (R) to achieve optimal shape complementary with SARS-CoV-2 Mpro PROTEIN. Lead optimization led to the discovery of 23R, which inhibits SARS-CoV-2 Mpro PROTEIN and SARS-CoV-2 viral replication with an IC50 of 0.31 microM and EC50 of 1.27 microM, respectively. The binding and specificity of 23R to SARS-CoV-2 Mpro PROTEIN were confirmed in a thermal shift assay and native mass spectrometry assay. The co-crystal structure of SARS-CoV-2 Mpro PROTEIN with 23R revealed the P2 biphenyl fits snuggly into the S2 pocket and the benzyl group in the -methylbenzyl faces towards the core of the enzyme, occupying a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study revealed the most potent non-covalent SARS-CoV-2 Mpro PROTEIN inhibitors reported to date and a novel binding pocket that can be explored for Mpro PROTEIN inhibitor design.

    Glycyrrhizin effectively neutralizes SARS-CoV-2 in vitro by inhibiting the viral main protease PROTEIN

    Authors: Lukas van de Sand; Maren Bormann; Mira Alt; Leonie Schipper; Christiane Silke Heilingloh; Daniel Todt; Ulf Dittmer; Carina Elsner; Oliver Witzke; Adalbert Krawczyk

    doi:10.1101/2020.12.18.423104 Date: 2020-12-20 Source: bioRxiv

    The newly emerged coronavirus, which was designated as severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the causative agent of the COVID-19 MESHD disease. High effective and well-tolerated medication for hospitalized and non-hospitalized patients is urgently needed. Traditional herbal medicine substances were discussed as promising candidates for the complementary treatment of viral diseases MESHD and recently suggested for the treatment of COVID-19 MESHD. In the present study, we investigated aqueous licorice root extract for its neutralizing activity against SARS-CoV-2 in vitro, identified the active compound glycyrrhizin and uncovered the respective mechanism of viral neutralization. We demonstrated that glycyrrhizin, the primary active ingredient of the licorice root, potently neutralizes SARS-CoV-2 by inhibiting the viral main protease PROTEIN. Our experiments highlight glycyrrhizin as a potential antiviral compound that should be further investigated for the treatment of COVID-19 MESHD.

    Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

    Authors: Maria Kuzikov; Elisa Costanzi; Jeanette Reinshagen; Francesca Esposito; Laura Vangeel; Markus Wolf; Bernhard Ellinger; Carsten Claussen; Gerd Geisslinger; Angela Corona; Daniela Iaconis; Carmine Talarico; Candida Manelfi; Rolando Cannalire; Giulia Rossetti; Jonas Gossen; Simone Albani; Francesco Musiani; Katja Herzog; Yang Ye; Barbara Giabbai; Nicola Demitri; Dirk Jochmans; Steven De Jonghe; Jasper Rymenants; Vincenzo Summa; Enzo Tramontano; Andrea Rosario Beccari; Pieter Leyssen; Paola Storici; Johan Neyts; Philip Gribbon; Andrea Zaliani

    doi:10.1101/2020.12.16.422677 Date: 2020-12-16 Source: bioRxiv

    Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection MESHD and COVID-19 MESHD disease. In this regard, SARS-CoV-2 main protease PROTEIN (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a HGNC and pp1 HGNCab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

    A blueprint for high affinity SARS-CoV-2 Mpro PROTEIN inhibitors from activity-based compound library screening guided by analysis of protein dynamics

    Authors: Jonas Goßen; Simone Albani; Anton Hanke; Benjamin P. Joseph; Cathrine Bergh; Maria Kuzikov; Elisa Costanza; Candida Manelfi; Paola Storici; Philip Gribbon; Andrea R. Beccari; Carmine Talarico; Francesca Spyrakis; Erik Lindahl; Andrea Zaliani; Paolo Carloni; Rebecca C. Wade; Francesca Musiani; Daria B. Kokh; Giulia Rossetti; Randeep Guleria; Krishna Ella; Balram Bhargava; Steven De Jonghe; Jasper Rymenants; Vincenzo Summa; Enzo Tramontano; Andrea Rosario Beccari; Pieter Leyssen; Paola Storici; Johan Neyts; Philip Gribbon; Andrea Zaliani

    doi:10.1101/2020.12.14.422634 Date: 2020-12-15 Source: bioRxiv

    The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease PROTEIN ( Mpro PROTEIN) is an attractive target for anti- COVID-19 MESHD agents. Unfortunately, unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ~30,000 SARS-CoV-2 Mpro PROTEIN conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ~200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's PROTEIN druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro PROTEIN blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro PROTEIN inhibitors to SARS-CoV-2 Mpro PROTEIN, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro PROTEIN, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro PROTEIN and a new computational approach to screen protein targets with malleable binding sites.

    Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture

    Authors: Khushboo Bafna; Kris White; Balasubramanian Harish; Romel Rosales; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.13.422511 Date: 2020-12-14 Source: bioRxiv

    Effective control of COVID-19 MESHD requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mpro PROTEIN and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro PROTEIN binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mpro PROTEIN protease activity, while four dock well into the PLpro PROTEIN substrate binding cleft MESHD and inhibit PLpro PROTEIN protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit Mpro PROTEIN, or both Mpro PROTEIN and PLpro PROTEIN, suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. HighlightsO_LISeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro PROTEIN and PLpro PROTEIN. C_LIO_LISeven HCV drugs inhibit Mpro PROTEIN enzyme activity, four HCV drugs inhibit PLpro PROTEIN. C_LIO_LISeven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells. C_LIO_LIHCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2. C_ LI eTOC blurbBafna MESHD, White and colleagues report that several available hepatitis C MESHD virus drugs inhibit the SARS-CoV-2 Mpro PROTEIN and/or PLpro PROTEIN proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/422511v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@d21075org.highwire.dtl.DTLVardef@13678edorg.highwire.dtl.DTLVardef@13d103aorg.highwire.dtl.DTLVardef@1f45fdb_HPS_FORMAT_FIGEXP M_FIG C_FIG

    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.

    Calotropin from milk of Calotropis gigantean a potent inhibitor of COVID 19 corona virus infection by Molecular docking studies

    Authors: Arun Dev Sharma; Inderjeet Kaur

    id:2012.06139v1 Date: 2020-12-11 Source: arXiv

    SARS-CoV-2 ( COVID-19 MESHD), a positive single stranded RNA virus, member of corona virus family, is spreading its tentacles across the world due to lack of drugs at present. Being associated with cough MESHD, fever MESHD, and respiratory distress, this disease caused more than 15 % mortality worldwide. Due to its vital role in virus replication, Mpro PROTEIN/ 3CLpro PROTEIN has recently been regarded as a suitable target for drug design. The current study focused on the inhibitory activity of Calotropin, a component from milk of Calotropis gigantean, against Mpro PROTEIN protein from SARS-CoV-2. Till date there is no work is undertaken on in-silico analysis of this compound against Mpro PROTEIN of COVID-19 MESHD protein. In the present study, molecular docking studies were conducted by using Patchdock tool. Protein Interactions tool was used for protein interactions. The calculated parameters such as docking score indicated effective binding of Calotropin to Mpro PROTEIN protein. Interactions results indicated that, Mpro PROTEIN/ Calotropin complexes forms hydrophobic interactions. Therefore, Calotropin may represent potential herbal treatment to act as COVID-19 MESHD Mpro PROTEIN inhibitor. However, further research is necessary to investigate their potential medicinal use.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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