Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes: an in silico perspective

Abstract Background Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. Discussion We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. Conclusion Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.

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In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm

PLoS ONE ◽

10.1371/journal.pone.0240149 ◽

2020 ◽

Vol 15 (10) ◽

pp. e0240149

Author(s):

Laura Artigas ◽

Mireia Coma ◽

Pedro Matos-Filipe ◽

Joaquim Aguirre-Plans ◽

Judith Farrés ◽

...

Keyword(s):

Respiratory Distress ◽

In Silico ◽

Drug Repurposing ◽

Cytokine Storm ◽

Promising Candidate

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Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes in silico

10.21203/rs.3.rs-329239/v1 ◽

2021 ◽

Author(s):

Gideon A. Gyebi ◽

Oludare M. Ogunyemi ◽

Ibrahim M. Ibrahim ◽

Saheed O. Afolabi ◽

Joseph O. Adebayo

Keyword(s):

In Silico ◽

Glucocorticoid Receptors ◽

Active Regions ◽

Binding Energies ◽

Dynamics Simulation ◽

Mode Analysis ◽

High Morbidity ◽

Cytokine Storm

Abstract The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and “cytokine storm” syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 106 steriodal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethason binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 Kcal/mol, was obtained and analyzed for interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated favourable druggable and in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.

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Are Losartan and Imatinib Effective Against SARS-CoV2 Pathogenesis? a Pathophysiologic-Based in Silico Study

10.26434/chemrxiv.12271865.v3 ◽

2020 ◽

Cited By ~ 1

Author(s):

Reza Nejat ◽

Ahmad Shahir Sadr

Keyword(s):

Life Cycle ◽

In Silico ◽

Cytokine Storm ◽

Mortality And Morbidity ◽

Death Toll ◽

In Silico Study ◽

Near Future

COVID19 has spread all over the globe with ARDS as the most grave complicating factor in its mortality and morbidity. As there is not an effective anti-viral drug or an imminent vaccine against this virus we proposed a novel insight about cytokine storm-indiced ARDS in this disease and conducted an in silico study according to the pathophysiology of cytokine storm. We found that losartan and imatinib may break the life cycle of the virus to the degree that its affinity to ACE2 may decline, the function of papin-like protease disrupts, and the cytokine storm may subside, as well. This means that the death toll of the disease may decline sharply till a vaccine is produced in the near future. All the results should be validated in subclinical studies.<div><div><br></div></div>

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Are Losartan and Imatinib Effective Against SARS-CoV2 Pathogenesis? a Pathophysiologic-Based in Silico Study

10.26434/chemrxiv.12271865.v2 ◽

2020 ◽

Cited By ~ 1

Author(s):

Reza Nejat ◽

Ahmad Shahir Sadr

Keyword(s):

Life Cycle ◽

In Silico ◽

Cytokine Storm ◽

Mortality And Morbidity ◽

Death Toll ◽

In Silico Study ◽

Near Future

COVID19 has spread all over the globe with ARDS as the most grave complicating factor in its mortality and morbidity. As there is not an effective anti-viral drug or an imminent vaccine against this virus we proposed a novel insight about cytokine storm-indiced ARDS in this disease and conducted an in silico study according to the pathophysiology of cytokine storm. We found that losartan and imatinib may break the life cycle of the virus to the degree that its affinity to ACE2 may decline, the function of papin-like protease disrupts, and the cytokine storm may subside, as well. This means that the death toll of the disease may decline sharply till a vaccine is produced in the near future. All the results should be validated in subclinical studies.<div><div><br></div></div>

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The predicted subcellular localisation of the sugarcane proteome

Functional Plant Biology ◽

10.1071/fp08252 ◽

2009 ◽

Vol 36 (3) ◽

pp. 242 ◽

Cited By ~ 5

Author(s):

Renato Vicentini ◽

Marcelo Menossi

Keyword(s):

In Silico ◽

Biological Function ◽

Plant Cells ◽

Subcellular Localisation ◽

Biological Processes ◽

Dual Targeting ◽

Genome Wide ◽

Increasing Knowledge

Plant cells are highly organised, and many biological processes are associated with specialised subcellular structures. Subcellular localisation is a key feature of proteins, since it is related to biological function. The subcellular localisation of such proteins can be predicted, providing information that is particularly relevant to those proteins with unknown or putative function. We performed the first in silico genome-wide subcellular localisation analysis for the sugarcane transcriptome (with 11 882 predicted proteins) and found that most of the proteins were localised in four compartments: nucleus (44%), cytosol (19%), mitochondria (12%) and secretory destinations (11%). We also showed that ~19% of the proteins were localised in multiple compartments. Other results allowed identification of a potential set of sugarcane proteins that could show dual targeting by the use of N-truncated forms that started from the nearest downstream in-frame AUG codons. This study was a first step in increasing knowledge about the subcellular localisation of the sugarcane proteome.

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Zika virus drug targets: a missing link in drug design and discovery – a route map to fill the gap

RSC Advances ◽

10.1039/c6ra12142j ◽

2016 ◽

Vol 6 (73) ◽

pp. 68719-68731 ◽

Cited By ~ 18

Author(s):

Pritika Ramharack ◽

Mahmoud E. S. Soliman

Keyword(s):

Drug Discovery ◽

Drug Design ◽

Viral Replication ◽

Zika Virus ◽

In Silico ◽

Drug Targets ◽

Missing Link ◽

Potential Inhibitors

This review depicts anin silicoroute map for ZIKV drug discovery, thus revealing novel potential inhibitors of viral replication.

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Chemical Composition of the Red Sea Green Algae Ulva lactuca: Isolation and In Silico Studies of New Anti-COVID-19 Ceramides

Metabolites ◽

10.3390/metabo11120816 ◽

2021 ◽

Vol 11 (12) ◽

pp. 816

Author(s):

Enas E. Eltamany ◽

Sameh S. Elhady ◽

Marwa S. Goda ◽

Omar M. Aly ◽

Eman S. Habib ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Replication ◽

Green Algae ◽

In Silico ◽

Biological Activities ◽

Antibacterial Activities ◽

Ulva Lactuca ◽

Organic Extract ◽

In Silico Studies ◽

High Resolution Mass Spectroscopy

Coronavirus disease 2019 (COVID-19) is the disease caused by the virus SARS-CoV-2 responsible for the ongoing pandemic which has claimed the lives of millions of people. This has prompted the scientific research community to act to find treatments against the SARS-CoV-2 virus that include safe antiviral medicinal compounds. The edible green algae U. lactuca. is known to exhibit diverse biological activities such as anti-influenza virus, anti-Japanese encephalitis virus, immunomodulatory, anticoagulant, antioxidant and antibacterial activities. Herein, four new ceramides in addition to two known ones were isolated from Ulva lactuca. The isolated ceramides, including Cer-1, Cer-2, Cer-3, Cer-4, Cer-5 and Cer-6 showed promising antiviral activity against SARS-CoV-2 when investigated using in silico approaches by preventing its attachment to human cells and/or inhibiting its viral replication. Cer-4 and Cer-5 were the most effective in inhibiting the human angiotensin converting enzyme (hACE)–spike protein complex which is essential for the virus to enter the human host. In addition to this, Cer-4 also showed an inhibition of the SARS-CoV-2 protease (Mpro) that is responsible for its viral replication and transcription. In this study, we also used liquid chromatography coupled to electrospray ionization high-resolution mass spectroscopy (LC–ESI–HRMS) to identify several metabolites of U. lactuca, including metabolites such as fatty acids, their glyceride derivatives, terpenoids, sterols and oxysterols from the organic extract. Some of these metabolites also possessed promising antiviral activity, as previously reported.

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Identification of Atovaquone and Mebendazole as Repurposed Drugs with Antiviral Activity against SARS-CoV-2 (Version 6)

10.33774/chemrxiv-2021-b3fv1-v7 ◽

2021 ◽

Author(s):

Mahmoud Ahmed ◽

Ayman Farag ◽

Ian N. Boys ◽

Ping Wang ◽

Jennifer L. Eitson ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Replication ◽

In Silico ◽

Covalent Binding ◽

Purine Metabolism ◽

Structure Based Drug Design ◽

Replication Assay ◽

Protease Enzyme ◽

Approved Drugs ◽

Fda Approved Drugs

Given the continuing heavy toll of the COVID-19 pandemic, therapeutic options for treatment are urgently needed. Here, we adopted a repositioning approach using in silico molecular modeling to screen FDA-approved drugs with established safety profiles for potential inhibitory effects against SARS-CoV-2. We used structure-based drug design to screen more than 2000 FDA approved drugs against SARS-CoV-2 main protease enzyme (Mpro) substrate-binding pocket. We additionally screened the top hits from both sites for potential covalent binding via nucleophilic thiol attack of Cys 145. High-scoring candidates were then screened for antiviral activity against infectious SARS-CoV-2 in a cell-based viral replication assay, and counter screened for toxicity. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. In addition, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 M), mebendazole (IC50 19 M) and entacapone (IC50 9 M). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential antiviral mechanisms. Although atovaquone is a known DHODH inhibitor, we did not observe inhibition of DHODH by atovaquone at concentrations relevant to the SARS-CoV-2 IC50. Interestingly, metabolomic profiling of atovaquone treated cells demonstrated marked dysregulation of metabolites in the purine metabolism pathway. In summary, a number of our top hits from the in-silico screen demonstrated Mpro inhibitory activity associated with antiviral effects. Atovaquone and mebendazole are the most promising candidates targeting SARS-CoV-2 from our screen, however atovaquone did not significantly inhibit Mpro at therapeutically meaningful concentrations but may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.

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