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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP3 (17)

NSP5 (7)

ProteinS (3)

ComplexRdRp (2)

NSP14 (1)


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SARS-CoV-2 Proteins
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    Protease-activatable biosensors of SARS-CoV-2 infection MESHD for cell-based drug, neutralisation and virological assays

    Authors: Pehuen Pereyra Gerber; Lidia M Duncan; Edward JD Greenwood; Sara Marelli; Adi Naamati; Ana Teixeira-Silva; Thomas WM Crozier; Ildar Gabaev; Jun R Zhan; Anna V Protasio; Nicholas J Matheson

    doi:10.1101/2021.03.22.435957 Date: 2021-03-22 Source: bioRxiv

    The world is in the grip of a severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) pandemic, and there is an urgent unmet clinical need for effective antiviral therapies. Many inhibitors of viral enzymes identified in vitro have limited efficacy against viral replication in cells, but conventional plaque assays are impractical for high-throughput screens. In this study, we therefore engineer cell-based biosensors of SARS-CoV-2 infection MESHD. Our assays exploit the cleavage of specific oligopeptide linkers by SARS-CoV-2 Main or Papain-like proteases PROTEIN, leading to the activation of green fluorescent protein (GFP) or firefly luciferase-based reporters. First, we characterise these biosensors in cells using recombinant viral proteases. Next, we confirm their ability to detect endogenous viral protease expression during infection with wildtype SARS-CoV-2. Finally, we develop a sensitive luminescent reporter cell line, confirm that it accurately quantitates infectious SARS-CoV-2 virus, and demonstrate its utility for drug screening and titration of neutralising antibodies.

    Novel Mutations in NSP1 HGNC and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics

    Authors: Mohammad Uzzal Hossain; Arittra Bhattacharjee; Md. Tabassum Hossain Emon; Zeshan Mahmud Chowdhury; Md. Golam Mosaib; Md. Moniruzzaman; Md. Hadisur Rahman; Md. Nazrul Islam; Irfan Ahmed; Md. Ruhul Amin; Asif Rashed; Keshob Chandra Das; Chaman Ara Keya; Md. Salimullah; Maria Elvira Balcells; Luis Rojas; Bruno Nervi; Jyh Kae Nien; Javier Garate; Carolina Prieto; Sofia Palma; Carolina Escobar; Josefina bascunan; Rodrigo Munoz; Monica Pinto; Daniela Cardemil; Marcelo Navarrete; Soledad Reyes; Victoria Espinoza; Nicolas Yanez; Christian Caglevic

    doi:10.1101/2020.12.02.408229 Date: 2020-12-02 Source: bioRxiv

    Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2), the etiologic agent of Coronavirus Disease MESHD- 2019 ( COVID-19 MESHD), is rapidly accumulating new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Recently, we have reported a Sanger method based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel mutations in V121D, V843F, A889V and G1691C positions. V121D substitution has the potential to destabilize the Non-Structural Protein ( NSP-1 HGNC) which inactivates the type-1 Interferon-induced antiviral system hence this mutant could be the basis of attenuated vaccines against SARS-CoV-2. V843F, A889V and G1691C are all located in NSP3 PROTEIN NSP3 HGNC. G1691C can decrease the flexibility of the protein while V843F and A889V changed the binding pattern of SARS-CoV-2 Papain MESHD Papain-Like protease PROTEIN (PLPro) inhibitor GRL0617. V843F PLPro showed reduced affinity for Interferon Stimulating Gene-15 ( ISG-15 HGNC) protein whereas V843F+A889V double mutants exhibited the same binding affinity as wild type PLPro. Here, V843F is a conserved position of PLPro that damaged the structure but A889V, a less conserved residue, most probably neutralized that damage. Mutants of NSP1 HGNC could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro could be targeted to develop anti-SARS therapeutics.

    Naturally occurring phytochemical as inhibitors from Catharanthus roseus: An In-silico approaches for drug development against COVID-19 MESHD

    Authors: Rishee K. Kalaria; Hiren K. Patel

    doi:10.21203/rs.3.rs-116443/v1 Date: 2020-11-26 Source: ResearchSquare

    The current outbreak of the novel 2019 Coronavirus disease MESHD ( COVID-19 MESHD) is caused by SARS-CoV-2, has developed a threat to the world's human population. There are no effective therapies or vaccines yet, urging the serious efforts to tackle this pandemic situation. SARS-CoV-2 spike PROTEIN protein, papain like protease PROTEIN protein (PLPRO), main protease PROTEIN ( 3CLpro PROTEIN) and RNA dependent DNA polymerase are key factors in the virus infectious process and have been identified as potential targets for therapeutic formulation. Most people in India depend on conventional Indian medicine (phytochemical compounds) to treat diseases MESHD due to lower cost, easier accessibility and no adverse effects. A lot of studies have recently shown that phytochemicals contain an effective anti-viral activity. This study aims to investigate phytochemicals metabolites from the IMPPAT database (Indian Medicinal Plants Database) in order to identify potential COVID-19 MESHD inhibitors using in silico approaches. Certain phytochemical compounds with structure analogs like hydroxychloroquine and chloroquine from the IMPPAT database were taken for interaction with SARS-CoV-2 proteins MESHD. The Apparicine, 12-Chlorotabersonine, AC1NSULH and Vindolininol identified from Catharanthus roseus were further checked the ADMET property as well as ‘Lipinski’s rule and resulted in a strong binding affinity of (-7.6,-7.5) and (-7.6 -7.5) kcal/mol respectively for spikes and papain like protease PROTEIN protein of SARS-CoV-2. Our results indicate that these specific compounds can be used as effective inhibitors and help to pace up the drug development against SARS-CoV-2. Further investigation and testing of these inhibitors against SARS‐CoV‐2 are however required to check their clinical trial candidacy.

    BCG vaccine derived peptides induce SARS-CoV-2 T cell cross-reactivity

    Authors: Peter J Eggenhuizen; Boaz H Ng; Janet Chang; Ashleigh L Fell; Wey Y Wong; Poh-yi Gan; Stephen R Holdsworth; Joshua D Ooi

    doi:10.1101/2020.11.21.20236018 Date: 2020-11-23 Source: medRxiv

    Epidemiological studies suggest that the Bacillus Calmette-Guerin (BCG) vaccine may have protective effects against coronavirus disease 2019 MESHD ( COVID-19 MESHD); and, there are now more than 15 ongoing clinical trials seeking to determine if BCG vaccination can prevent or reduce the severity of COVID-19 MESHD (1). However, the mechanism by which BCG vaccination can induce a severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) specific T cell response is unknown. Here, in silico, we identify 8 BCG derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 MESHD NSP3 PROTEIN NSP3 HGNC or NSP13 PROTEIN derived peptides. Using an in vitro co-culture system, we show that human CD4 HGNC+ and CD8 HGNC+ T cells primed with a BCG derived peptide developed enhanced reactivity to its corresponding SARS-CoV-2 derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2 derived peptides. These findings provide a mechanistic basis for the epidemiologic observation that BCG vaccination confers protection from COVID-19 MESHD; and supports the use of BCG vaccination to induce cross-reactive SARS-CoV-2 specific T cell responses.

    Molecular Docking and ADMET studies of Allium cepa, Azadirachta indica and Xylopia aethiopica isolates as potential anti-viral drugs for Covid-19 MESHD

    Authors: Peter Ifeoluwa Adegbola; Banjo Semire; Olumide Samuel Fadahunsi; Aanuoluwa Eunice Adegoke

    doi:10.21203/rs.3.rs-100161/v1 Date: 2020-10-29 Source: ResearchSquare

    Purpose: Plants are repository of important constituents with proven efficacy against many human diseases including viral diseases. The antiviral activity of many plants including Azadirachta indica, Xylopia aethiopica and Allium cepa has been reported. The novel coronavirus disease MESHD is no exception among viral diseases in which plant compounds could serve as potent antagonist. Therefore, our study investigated the inhibitory potentials of Azadirachta indica and Xylopia aethiopica isolates against SARS-CoV-2 viral accessory proteins and the host serine protease.Methods: The protein data (SARS-CoV-2 Papain like protease PROTEIN ( PLpro PROTEIN) (PDB: 6wx4), Chymotrypsin-like main protease PROTEIN ( 3CLpro PROTEIN) (PDB:6YB7), SARS-CoV nsp 12 (PDB: 6nus), Host cell protease (TMPRSS1) (PDB:5ce1) were obtained from the Protein Data Bank (PDB), while the SDS format of each Ligands were obtained from Pubchem database. Molecular docking analysis was performed with Auto Dock Vina 1.5.6 and visualization of the interaction between the ligands and protein was done with discovery studio 2019. The ADMET prediction of pharmacokinetics and toxicity properties of the ligands was obtained using vNN Web Server.Results: Our result showed that all the plant isolates demonstrated negative Gibb’s free energy, indicating good binding affinity for both the viral and host protein. Overall, twenty-three of the forty-seven isolates showed good binding affinity comparable with dexamethasone that was used as reference drug. Although many of the compounds have good binding affinity for the viral and host proteins, based on the ADMET prediction, only Azadironic acid, Nimbionone, Nimbionol and Nimocinol all from A. indica could serve as potential drug candidate with good pharmacokinetics and toxicity profile.  Conclusion: This study provides an insight into potential inhibitors and novel drug candidates for SARS-CoV-2.

    The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting viral replication-transcription complex in culture cells

    Authors: Shutoku Matsuyama; Miyuki Kawase; Naganori Nao; Kazuya Shirato; Makoto Ujike; Wataru Kamitani; Masayuki Shimojima; Shuetsu Fukushi; Dennis de Meulder; Peter van Run; Mart M Lamers; Bart Rijnders; Casper Rokx; Frank J.M. van Kuppeveld; Frank Grosveld; Dubravka Drabek; Corine GeurtsvanKessel; Marion Koopmans; Berend Jan Bosch; Thijs Kuiken; Barry Rockx; Greggory E Mojares; Michael P Eagan; Kristy L Ziontz; Paul Mastrokyriakos; Stuart L Goldberg; Felecia Cerrato; Maha Farhat; Damien Slater; Jason B Harris; John Branda; David Hooper; Jessie M Gaeta; Travis P. Baggett; James O'Connell; Andreas Gnirke; Tami D Lieberman; Anthony Philippakis; Meagan Burns; Catherine Brown; Jeremy Luban; Edward T Ryan; Sarah E Turbett; Regina C LaRocque; William P. Hanage; Glen Gallagher; Lawrence C Madoff; Sandra Smole; Virginia M. Pierce; Eric S Rosenberg; Pardis Sabeti; Daniel J Park; Bronwyn L MacInnis

    doi:10.1101/2020.08.22.258459 Date: 2020-08-24 Source: bioRxiv

    We screened steroid compounds to obtain a drug expected to block host inflammatory responses and MERS-CoV replication. Ciclesonide, an inhaled corticosteroid, suppressed replication of MERS-CoV MESHD and other coronaviruses, including SARS-CoV-2, the cause of COVID-19 MESHD, in cultured cells. The effective concentration (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 M. Ciclesonide inhibited formation of double membrane vesicles, which anchor the viral replication-transcription complex in cells. Eight consecutive passages of 43 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single amino acid substitutions in non-structural protein 3 PROTEIN ( nsp3 HGNC) or nsp4 HGNC. Of note, ciclesonide still suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade. These observations indicate that the suppressive effect of ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the treatment of COVID-19 MESHD patients. ImportanceThe outbreak of SARS-CoV-2, the cause of COVID-19 MESHD, is ongoing. To identify the effective antiviral agents to combat the disease is urgently needed. In the present study, we found that an inhaled corticosteroid, ciclesonide suppresses replication of coronaviruses, including beta-coronaviruses (MHV-2, MERS-CoV, SARS-CoV, and SARS-CoV-2) and an alpha-coronavirus (HCoV-229E) in cultured cells. The inhaled ciclesonide is safe; indeed, it can be administered to infants at high concentrations. Thus, ciclesonide is expected to be a broad-spectrum antiviral drug that is effective against many members of the coronavirus family. It could be prescribed for the treatment of MERS, and COVID-19 MESHD.

    Reappraisal of Trifluperidol against NSP-3 HGNC protein: Potential therapeutic for COVID-19 MESHD

    Authors: Ajita Pandey

    doi:10.21203/rs.3.rs-52706/v1 Date: 2020-08-03 Source: ResearchSquare

    Novel coronavirus disease 2019 MESHD ( COVID-19 MESHD) is a highly infectious disease MESHD that is caused by the recently discovered severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2). Because there are no specific vaccines or drugs for SARS-CoV-2, drug repurposing may be a promising approach. SARS-CoV-2 has a positive-sense RNA genome that encodes non-structural proteins (Nsps), which are essential for viral replication in the host cell. Non-structural protein 3 PROTEIN ( Nsp3 HGNC) is a multidomain protein and is the largest protein of the replicase complex. Nsp3 HGNC contains an ADP-ribose phosphatase ( ADRP HGNC) domain, also called the macrodomain, which interferes with the host immune response. In the present study, we used computational regression methods to target the ADRP HGNC domain of Nsp3 HGNC, using FDA-approved drugs. We virtually screened 2,892 FDA-approved drugs, using a combination of molecular docking and scoring functions. Saquinavir and trifluperidol were identified as potential leads and were further investigated using molecular dynamics simulation (MDS) to predict the stability and behavior of the ADRP HGNC-drug complexes. Analysis of root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and number of hydrogen bonds showed that the ADRP HGNC-trifluperidol complex is more stable than the ADRP HGNC-saquinavir complex.  The screening and the MDS results suggest that trifluperidol is a novel inhibitor of the ADRP HGNC domain of Nsp3 HGNC. Trifluperidol could, therefore, potentially be used to help control the spread of COVID-19 MESHD, either alone or in combination with antiviral agents. Further in-vitro and in-vivo experiments are necessary to confirm our in silico results.

    Assessment of Proton-Coupled Conformational Dynamics of SARS and MERS Coronavirus Papain-like Proteases PROTEIN: Implication for Designing Broad-Spectrum Antiviral Inhibitors

    Authors: Jack A Henderson; Neha Verma; Jana Shen

    doi:10.1101/2020.06.30.181305 Date: 2020-07-01 Source: bioRxiv

    Broad-spectrum antiviral drugs are urgently needed to stop the COVID-19 MESHD COVID-19 MESHD pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) MESHD, which have caused the previous outbreaks. The papain-like protease PROTEIN ( PLpro PROTEIN) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro PROTEIN is rich in cysteines and histidines and their protonation/deprotonation modulates catalysis and conformational plasticity. Here we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV MESHD and MERS-CoV PLpros using a newly developed GPU-accelerated implicit-solvent continuous constant pH molecular dynamics method with an asynchronous replica-exchange scheme. The calculated pKa’s support the catalytic roles of the Cys-His-Asp triad. We also found that several residues can switch protonation states at physiological pH, among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro PROTEIN. Simulations revealed that the BL2 conformational dynamics is coupled to the titration of C271/270, in agreement with the crystal structures of SARS-CoV-2 PLpro PROTEIN. Simulations also revealed that BL2 in MERS-CoV PLpro PROTEIN is very flexible, sampling both open and closed states despite the lack of an analogous cysteine. Our work provides a starting point for more detailed mechanistic studies to assist structure-based design of broad-spectrum inhibitors against CoV PLpros.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    A rational drug designing: What bioinformatics approach tells about the wisdom of practicing traditional medicines for screening the potential of Ayurvedic and natural compounds for their inhibitory effect against COVID-19 MESHD Spike, Indian strain Spike, Papain-like protease PROTEIN and Main Protease PROTEIN protein

    Authors: Prashant Ranjan; Bhagyalaxmi Mohapatra; Parimal Das

    doi:10.21203/rs.3.rs-30366/v1 Date: 2020-05-19 Source: ResearchSquare

    The new outbreak of Coronavirus disease MESHD ( COVID-19 MESHD) has been entitled as a pandemic by W.H.O. It spreads to almost 211 countries due to its contagious nature. There is an urgent need for developing specific therapeutic agents against COVID-19 MESHD. We have performed virtual screening of 52 ligands; most of which are essential components of traditional Ayurvedic medicine as well as natural compounds and three were standard repurposing drugs against COVID-19 MESHD Spike, Indian strain Spike (IS-Spike), PL-Pro and M-Pro to find potential inhibitor effects. Based on the docking results, it is estimated that compounds have a better binding affinity with M-Pro and PL-Pro than Spike as well as IS-Spike so it can be beneficial as therapeutics against COVID-19 MESHD. We also conclude that the binding affinity of ligands with IS-Spike gets low as compared to Spike so the inhibitory potential of drugs may get weak. Based on the calculation of average binding energy (B.E) with the three targets, Spike, PL-Pro, and M-Pro, we found10 best ligands viz. (1) Punicafolin (2) Emblicanin A (3) Punigluconin (4) Lopinavir (5) Kuwanon X (6) Rutin (7) Lithospermic Acid (8) Phyllanemblinin A (9) Amarogentin and (10) Amaroswerin for inhibition. These ligands may act as potential inhibitors against COVID-19 MESHD druggable tri-targets. Network analysis revealed that four ligands out of 10 leading compounds are common in all four different networks (Spike, IS-Spike, PL-Pro, and M-Pro) which come under Phyllanthus emblica. Notably, a compound of Azadirachta indica out of 4 and a single compound of Swertia chirata was found common in all networks. Additionally, a standard drug Lopinavir and a compound of Salvia miltiorrhiza are frequently found in all networks. In principle, it appears plausible that the compounds which are common in the entire network should have more inhibitory potential against COVID19 MESHD due to the better binding potential among all targets, thus providing better candidacy for drug development. 

    Molecular Docking Analyses of Phytochemicals Obtained from African Antiviral Herbal Plants Exhibit Inhibitory Activity against Therapeutic Targets of SARS-CoV-2

    Authors: Goni AbrahamDogo; Ohaeri Uchechukwu; Uzal Umar; Aboi J. Madaki; John C. Aguiyi

    doi:10.21203/rs.3.rs-28666/v1 Date: 2020-05-12 Source: ResearchSquare

    Presently, the global public health threat of international concern is the coronavirus disease-2019 ( COVID-19 MESHD), a viral disease of worldwide prevalence caused by severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), at present the disease has no known cure or vaccine. Plants worldwide including plants of African ethnopharmacological relevance are a natural source of abundant and diverse phytochemicals with bioactivity against microorganisms including viruses. We selected 13 plants used in African traditional medicine for the treatment of viral diseases to screen for phytochemicals capable of interfering with SARS-CoV-2 therapeutic targets using AutoDock Vina in silico tool. 25 phytochemicals from these plants that passed the Lipinski rule of drug-likeness were assessed for antiviral activity against three SARS-CoV-2 therapeutic targets, namely: spike glycoprotein PROTEIN, Papain-like protease PROTEIN and 3C-like proteinase. The crystal structure of the viral protein targets was obtained from the protein databank website (https://www.rcsb.org/). The active sites of the target proteins were predicted using SCFBio Server (http://www.scfbio-iitd.res.in/dock/ActiveSite.jsp) from the PDB file as input. The antiviral herbal phytochemical compounds were then docked with prepared targets: Papain-like protease PROTEIN, 3C-like proteinase and spike glycoprotein PROTEIN. The Autodocking hit results generated six lead phytochemicals out of a library of twenty-five (25) phytochemicals from the African traditional herbs with potential anti-SARS-CoV-2 activity. The lead molecules with their binding affinities against Papain-like protease PROTEIN and 3C-Like Proteinase are as follows: Ginsenosides (-9.9 kcal/mol), ursolic acid (-9.4 kcal/mol), oleanolic acid (-9.4 kcal/mol), cynarine (-8.9 kcal/mol), glabridin (-8.5 kcal/mol) and cinnamoyl-echinadiol (-8.2 kcal/mol). ADMET profile shows glabridin, cinnamoyl-echinadiol and neral obtained from Licorice, Echinacea purpurea and lemongrass respectively, exhibited best-fit values as drugs candidate. We advocate for further in vitro and in vivo studies to evaluate the activity of these lead compounds with a view to optimized drug intervention against COVID-19 pandemic MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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