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Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (28)

ProteinS (9)

ComplexRdRp (6)

NSP3 (3)

NSP9 (1)


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SARS-CoV-2 Proteins
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    N-Terminal finger stabilizes the reversible feline drug GC376 in SARS-CoV-2 Mpro PROTEIN

    Authors: Elena Arutyunova; Muhammad Bashir Khan; Conrad Fischer; Jimmy Lu; Tess Lamer; Wayne Vuong; Marco J van Belkum; Ryan T McKay; D. Lorne Tyrrell; John C Vederas; Howard S Young; M Joanne Lemieux

    doi:10.1101/2021.02.16.431021 Date: 2021-02-16 Source: bioRxiv

    The main protease PROTEIN ( Mpro PROTEIN, also known as 3CL protease PROTEIN) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 MESHD infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease PROTEIN and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease PROTEIN of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity MESHD due to off-target effects. Here we demonstrate that GC376 has nanomolar Ki values with the Mpro from both SARS-CoV-2 PROTEIN and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro PROTEIN. The comparison of a new X-ray crystal structure of Mpro PROTEIN from SARS-CoV MESHD complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro PROTEIN, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro PROTEIN, which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.

    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.

    In Vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against Sars-Cov2 Strain Isolated From Egyptian Patients

    Authors: Mohamed G Seadawy; Ahmed F. Gad; Mohamed Shamel; Bassem Elharty; Mostfa F. Mohamed; Abdo A. Elfiky; Aya Ahmed; Abdel Rahman N. Zekri

    doi:10.21203/rs.3.rs-119568/v1 Date: 2020-12-01 Source: ResearchSquare

    Background: The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Methods: Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. Results: The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)Conclusion: Development of an effective anti-viral for SARS-CoV-2  could help to limit the viral load. Benchmarking testing of those natural compounds against other potential antivirals for SARS-CoV-2 with alternative mechanisms of action would thus be important as soon as practicable.

    in vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against SARS-CoV2 Strain Isolated From Egyptian Patients

    Authors: Mohamed Gomaa Seadawy; Ahmed F Gad; Bassem E Harty; Mostfa Fetooh Mohamed; Mohamed Shamel ELdesoky; Abdo A Elfiky; Aya Ahmed; Abdel N Zekri; Elitza S Theel; Ali H Ellebedy; Daved H Fremont; Michael S Diamond; Sean P. J. Whelan; Gius Kerster; Hannah L Turner; Karlijn van der Straten; Cynthia A. van der Linden; Yoann Aldon; Thibaut Naninck; Ilja Bontjer; Judith A. Burger; Meliawati Poniman; Anna Z Mykytyn; Nisreen M.A. Okba; Edith E. Schermer; Marielle J. van Breemen; Rashmi Ravichandran; Tom G. Caniels; Jelle van Schooten; Nidhal Kahlaoui; Vanessa Contreras; Julien Lemaitre; Catherine Chapon; Raphael Ho Tsong Fang; Julien Villaudy; Kwinten Sliepen; Yme U. van der Velden; Bart Haagmans; Godelieve J. de Bree; Eric Ginoux; Andrew B. Ward; Max Crispin; Neil P King; Sylvie van der Werf; Marit J. van Gils; Roger Le Grand; Rogier W. Sanders

    doi:10.1101/2020.11.07.367649 Date: 2020-11-08 Source: bioRxiv

    The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)

    Identification of Potential Phytochemical Inhibitors as Promising Therapeutics Against SARS-CoV-2 and Molecular Dynamics Simulation

    Authors: Anik Banik; Emran Sajib; Anamika Deb; Sheikh Rashel Ahmed; Md- Tariqul Islam; Soykot Roy; Shiuly Sinha; Hlamrasong Marma; Kazi Faizul Azim

    doi:10.26434/chemrxiv.13182965.v1 Date: 2020-11-04 Source: ChemRxiv

    The high infectivity and mortality of novel coronavirus has caused a serious concern all over the world. Still, there is no specific drug or preventive medication to treat SARS-CoV-2 infection MESHD despite comprehensive analysis by the researchers. This study was designed to demonstrate the efficacy of some phyto-chemical compounds against SARS-CoV-2 by using both structure and ligand based virtual screening methods. A total of 33 plant metabolites were screened against SARS-CoV-2 main protease PROTEIN proteins (MPP), Nsp9 RNA binding protein, spike PROTEIN receptor binding domain and HR2 domain using a molecular docking approach. Results showed that three metabolites, i.e., Limonin, Isoflavone, and Coumadin conferred maximum binding affinity with all key proteins of SARS-CoV-2. For each viral protein, the critical binding sites and drug surface hotspots have been unraveled. ADME analysis indicated that none of the compounds have adverse effects that could decrease their drug-like properties. Moreover, toxicity MESHD pattern analysis also unmasked the non-toxic nature of the top drug candidates. The RMSD values of top ligandmacromolecule complexes were less than 2 Å, while RMSF values showed regular atomic fluctuations in the molecular dynamics study. Notably, most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases, protease, Kinase). Results of drug similarity prediction revealed two approved structural analogs of Coumadin named Warfarin (DB00682) and Phenprocoumon (DB00946) from DrugBank. In addition, Isoformononetin an experimental drug analog of isoflavone could also be an option for the treatment of viral infections MESHD. For limonin there was no analog found in drugbank. The study can pave the way for the creation of effective SARS-CoV-2 medications and preventive measures. We highly recommend further in vivo trials for the experimental validation of our findings

    Natural Compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) Against SARS-CoV-2 Strain Isolated From Egyptian Patients

    Authors: Mohamed Seadawy

    doi:10.21203/rs.3.rs-101405/v1 Date: 2020-11-01 Source: ResearchSquare

    The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)

    A cysteine protease inhibitor blocks SARS-CoV-2 infection MESHD of human and monkey cells

    Authors: Drake Mellott; Chien-Te Tseng; Aleksandra Drelich; Pavla Fajtova; Bala C Chenna; Demetrios Kostomiris; Jason C Hsu; Jiyun Zhu; Zane Taylor; Vivian Tat; Ardala Katzfuss; Linfeng Li; Miriam A Giardini; Danielle Skinner; Ken Hirata; Sungjun Beck; Aaron F Carlin; Alex E. Clark; Laura Berreta; Daniel Maneval; Felix Frueh; Brett L Hurst; Hong Wang; Klaudia I Kocurek; Frank M Raushel; Jair L. Siqueira-Neto; Thomas D Meek; James H McKerrow

    doi:10.1101/2020.10.23.347534 Date: 2020-10-24 Source: bioRxiv

    K777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ ACE2 HGNC, Caco-2, A549/ ACE2 HGNC, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ ACE2 HGNC, and 4 nM for HeLa/ ACE2 HGNC cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity MESHD of K777 was observed for any of the host cells at 10-100 M inhibitor. K777 did not inhibit activity of the papain- like cysteine protease PROTEIN and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of [≤] 100 M. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike PROTEIN protein and K777 blocked this proteolysis. The site of spike protein PROTEIN cleavage by cathepsin L was in the S1 domain of SARS-CoV-2 , differing from the cleavage site observed in the SARS CoV-1 spike protein PROTEIN. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein PROTEIN processing.

    Duple extinguishment of COVID-19 MESHD: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

    Authors: Xueyun Gao; Yong Gong; Wenjie Tan; Huaidong Jiang; Jianxun Qi; Jincun Zhao; Bo Sun; Xingfa Gao; Xuejiao Gao; Peng Cao; Bo He; Jiadong Fan; Yuhui Dong; Fuping Gao; Qing Yuan; Yucong Gao; Wencong Zhao; Chunyu Zhang; Zhongying Du; Fei Ye; Zhesheng He; Timothy H. Burgess; Christopher C. Broder; Graham Lord; Timothy Felton; Chris Brightling; Ling-Pei Ho; - NIHR Respiratory TRC; - CIRCO; Karen Piper Hanley; Angela Simpson; John R Grainger; Tracy Hussell; Elizabeth R Mann

    doi:10.1101/2020.10.16.342097 Date: 2020-10-16 Source: bioRxiv

    The virus replication and lung inflammation MESHD are basic targets for COVID-19 MESHD treatment. To effectively treat COVID-19 MESHD, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro PROTEIN. GA or AF could well inhibit Mpro PROTEIN activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NF{kappa}B pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1{beta}, TNF- in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 MESHD mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 MESHD mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury MESHD compared with NS treated COVID-19 MESHD mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity MESHD results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.

    Facing COVID-19 MESHD via anti-inflammatory mechanism of action: Molecular docking and Pharmacokinetic studies of six anti-inflammatory compounds derived from Passiflora edulis

    Authors: Aristote Matondo; Jason T Kilembe; Domaine T Mwanangombo; Beaudrique M Nsimba; Benjamin Z Gbolo; Gedeon N Bongo; Koto-te-Nyiwa Ngbolua; Dorothée D Tshilanda; Damien S T Tshibangu; Virima Mudogo; Pius T Mpiana

    doi:10.21203/rs.3.rs-87703/v1 Date: 2020-10-04 Source: ResearchSquare

    SARS-CoV-2 is the causative agent of the COVID-19 MESHD disease. Pathophysiologically, high levels of proinflammatory cytokines in the serum of SARS-CoV-2 patients are reported, which is so-called the cytokine storm. In this study, molecular docking calculations of six bioactive compounds from Passiflora edulis with anti-inflammatory activity in interaction with the main protease PROTEIN of SARS-CoV-2 were performed, and their pharmacokinetic properties were predicted. The results of their molecular simulations and the ADME-T profiles of each ligand (Absorption, Distribution, Metabolism, Excretion and Toxicity MESHD) suggest their use as potential treatment for SARS-CoV-2. Among the six investigated compounds in which four flavonoids and two alkaloids, the best docked ligands are quercetin (-8.2 kcal/mol), chrysin (-8.0 kcal/mol), kaempferol (-7.9 kcal/mol) and luteolin (-7.7 kcal/mol), both flavonoids compounds. Their pharmacokinetic studies using SwissADME, preADMET and pkCSM Web servers establish the good ADMET profile for each ligand.

    Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease PROTEIN by tafenoquine in vitro

    Authors: Yeh Chen; Wen-Hao Yang; Li-Min Huang; Yu-Chuan Wang; Chia-Shin Yang; Yi-Liang Liu; Mei-Hui Hou; Chia-Ling Tsai; Yi-Zhen Chou; Bao-Yue Huang; Chian-Fang Hung; Yu-Lin Hung; Jin-Shing Chen; Yu-Ping Chiang; Der-Yang Cho; Long-Bin Jeng; Chang-Hai Tsai; Mien-Chie Hung

    doi:10.1101/2020.08.14.250258 Date: 2020-08-15 Source: bioRxiv

    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 MESHD ( COVID-19 MESHD), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19 MESHD. Mpro PROTEIN has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of Mpro PROTEIN blocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 Mpro PROTEIN and diminishes its protease activity. Specifically, TFQ reduces the alpha-helical content of Mpro PROTEIN, which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection MESHD in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 Mpro PROTEIN. Moreover, the low clinical toxicity MESHD of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.

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