Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and
                        COVID-19

Sorbera, L. A.; Graul, A.; Dulsat, C.

doi:10.1358/dof.2020.45.4.3150676

Cited by 18 publications

(15 citation statements)

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“…Possible drug targets for the treatment of COVID-19 are currently under active investigation. These targets include; the Human coronavirus (SARS-CoV-2; COVID-19) proteins, membrane glycoprotein, Nucleocapsid, tumor necrosis factor receptor type 6, toll-like receptor 3, surface glycoprotein (spike glycoprotein), Interleukin-6 receptor subunit α (IL-6RA), and RNA-directed RNA polymerase (Sorbera et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Computational insight of dexamethasone against potential targets of SARS-CoV-2

Fadaka

Sibuyi

Madiehe

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The health sector has been on the race to find a potent therapy for coronavirus disease (COVID)-19, a diseases caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Repurposed anti-viral drugs have played a huge role in combating the virus, and most recently, dexamethasone (Dex) have shown its therapeutic activity in severe cases of COVID-19 patients. The study sought to provide insights on the anti-COVID-19 mechanism of Dex at both atomic and molecular level against SARS-CoV-2 targets. Computational methods were employed to predict the binding affinity of Dex to SARS-CoV-2 using the Schrodinger suite (v2020-2). The target molecules and ligand (Dex) were retrieved from PDB and PubChem, respectively. The selected targets were SARS-CoV-2 main protease (Mpro), and host secreted molecules glucocorticoid receptor, and Interleukin-6 (IL-6). Critical analyses such as Protein and ligand preparation, molecular docking, molecular dynamic (MD) simulations, and absorption, distribution, metabolism, excretion (ADME), and toxicity analyses were performed using the targets and the ligand as inputs. Dex showed stronger affinity to its theoretical (glucocorticoid) receptor with a superior docking score of À14.7 and a good binding energy value of À147.48 kcal/mol; while short hydrogen bond distances were observed in both Mpro and IL-6 when compared to glucocorticoid receptor. Based on these findings, Dex-target complexes were used to perform MD simulations to analyze Dex stability at 50 ns. This study demonstrates that Dex could bind to both the viral and host receptors as a potential drug candidate for COVID-19. To ascertain the biological fitness of this study, other SARS-CoV-2 targets should be explored. Also, the in vitro studies of dexamethasone against several SARS-CoV-2 targets warrant further investigation.

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Section: Introductionmentioning

confidence: 99%

Computational insight of dexamethasone against potential targets of SARS-CoV-2

Fadaka

Sibuyi

Madiehe

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…More importantly, a possible interaction of viral Orf8 with a variety of host proteins including FasL may explain the rapid spread of the coronavirus and immune evasion, since Orf8 of SARS-CoV-2 is highly secreted and downregulated MHC-I in cells [46]. A recent study by Sorbera et al [47] on speci c SARS-CoV-2-induced targets reported Fas-FasL signaling involved with endothelial function and neutrophil lifespan and related SARS-CoV-induced apoptosis with potential viral replication. Thus, inhibiting Fas/FasL interaction may be useful in the treatment of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

The aging whole blood transcriptome reveals a potential role of FASLG in COVID-19

Chuffa

Freire

Souza

et al. 2021

Preprint

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The risk for severe COVID-19 increases with age as older patients are at the highest risk. Identifying how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) interacts with blood components during aging is urgent. We investigated the aging whole blood transcriptome from the Genotype-Tissue Expression (GTEx) database to explore differentially expressed genes (DEGs) translated into proteins interacting with viral proteins. From 22 DEGs in aged blood, FASLG, CTSW, CTSE, VCAM1, and BAG3 changed their expression with involvement in immune response, inflammation, cell component and adhesion, and platelet activation/aggregation. Males and females older than 50 overexpress FASLG possibly inducing a hyper-inflammatory cascade. The expression of cathepsins (CTSW and CTSE) and the anti-apoptotic co-chaperone molecule BAG3 was increased throughout aging in both gender. By exploring publicly available Single-Cell RNA-Sequencing data on peripheral blood of SARS-CoV-2-infected patients, we found FASLG and CTSW expressed in natural killer cells and CD8 + T lymphocytes, whereas BAG3 was expressed in CD4 + T cells, naive T cells, and CD14 + monocytes. The expression of FASLG in aged blood may explain why older patients are more prone to viral infection complications. The results indicate FASLG as a prognostic candidate and potential therapeutic target for the more aggressive clinical manifestation of COVID-19. The reduction of FASLG could be helpul against disease progression.

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“…However, it appears that in presenting stages of Covid-19 disease antiviral agents seem to have questionable therapeutic benefit, possibly due to the disease entering an immunopathological stage of exuberant lymphocytic response ( 19 ). Sorbera et al claim SARS-Cov-induced apoptosis via a caspase-dependent mechanism may suggest inhibition of the Fas/FasL interaction may have efficacy in Sars-Cov-2, but the rationale disregards differentiation ( 45 ). Finally, in a CRISPR-Cas9 lentiviral vector knock out of GM-CSF in CAR T cells, Fas expression was significantly inhibited, which the authors argue would reduce CAR-T apoptosis ( 46 ), and GM-CSF inhibition trials are undergoing.…”

Section: Discussionmentioning

confidence: 99%

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

Leonardi

Proenca

2020

Front. Immunol.

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Aberrant T cell differentiation and lymphopenia are hallmarks of severe COVID-19 disease. Since T cells must race to cull infected cells, they are quick to differentiate and achieve cytotoxic function. With this responsiveness, comes hastened apoptosis, due to a coupled mechanism of death and differentiation in both CD4+ and CD8+ lymphocytes via CD95 (Fas) and serine-threonine kinase (Akt). T cell lymphopenia in severe cases may represent cell death or peripheral migration. These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response. Whether preservation of T cells, prevention of their aberrant differentiation, and expansion of their population may alter disease course is unknown. Its investigation requires experimental interrogation of the linked differentiation and death pathway by agents known to uncouple T cell proliferation and differentiation in both CD4+ and CD8+ T cells.

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Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19

Cited by 18 publications

References 0 publications

Computational insight of dexamethasone against potential targets of SARS-CoV-2

Computational insight of dexamethasone against potential targets of SARS-CoV-2

The aging whole blood transcriptome reveals a potential role of FASLG in COVID-19

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

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