scholarly journals Inhibiting the reproduction of SARS-CoV-2 through perturbations in human lung cell metabolic network

2020 ◽  
Vol 4 (1) ◽  
pp. e202000869
Author(s):  
Hadrien Delattre ◽  
Kalesh Sasidharan ◽  
Orkun S Soyer
Keyword(s):  
Metabolic Flux ◽  
Human Lung ◽  
Structural Information ◽  
Experimental Testing ◽  
Metabolic Model ◽  
Emerging Viruses ◽  
Nucleotide Biosynthesis ◽  
Human Lung Cells ◽  
Balance Analysis ◽  
Biomass Function

Viruses rely on their host for reproduction. Here, we made use of genomic and structural information to create a biomass function capturing the amino and nucleic acid requirements of SARS-CoV-2. Incorporating this biomass function into a stoichiometric metabolic model of the human lung cell and applying metabolic flux balance analysis, we identified host-based metabolic perturbations inhibiting SARS-CoV-2 reproduction. Our results highlight reactions in the central metabolism, as well as amino acid and nucleotide biosynthesis pathways. By incorporating host cellular maintenance into the model based on available protein expression data from human lung cells, we find that only few of these metabolic perturbations are able to selectively inhibit virus reproduction. Some of the catalysing enzymes of such reactions have demonstrated interactions with existing drugs, which can be used for experimental testing of the presented predictions using gene knockouts and RNA interference techniques. In summary, the developed computational approach offers a platform for rapid, experimentally testable generation of drug predictions against existing and emerging viruses based on their biomass requirements.

scholarly journals Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2437
Author(s):  
Bruno A. Rodriguez-Rodriguez ◽  
Maria G. Noval ◽  
Maria E. Kaczmarek ◽  
Kyung Ku Jang ◽  
Sara A. Thannickal ◽  
...  
Keyword(s):  
Human Lung ◽  
Direct Interaction ◽  
Holistic Medicine ◽  
Lung Cells ◽  
Emerging Viruses ◽  
Berberine Chloride ◽  
Human Lung Cells ◽  
Emerging Virus ◽  
To Come

Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.

scholarly journals RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells

2021 ◽  
Author(s):  
Taisho Yamada ◽  
Seiichi Sato ◽  
Yuki Sotoyama ◽  
Yasuko Orba ◽  
Hirofumi Sawa ◽  
...  
Keyword(s):  
Human Lung ◽  
Lung Cells ◽  
Human Lung Cells

scholarly journals Polyphosphate Reverses the Toxicity of the Quasi-Enzyme Bleomycin on Alveolar Endothelial Lung Cells In Vitro

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 750
Author(s):  
Werner E. G. Müller ◽  
Meik Neufurth ◽  
Shunfeng Wang ◽  
Heinz C. Schröder ◽  
Xiaohong Wang
Keyword(s):  
Dna Damage ◽  
Human Lung ◽  
Dna Integrity ◽  
Lung Cells ◽  
Antitumor Antibiotic ◽  
Cell Toxicity ◽  
Inorganic Polyphosphate ◽  
Human Lung Cells ◽  
Anti Cancer

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml−1 causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold). Importantly, the BLM-caused effects on cell growth and DNA integrity are substantially suppressed by polyP. In parallel, the enlargement of the nuclei/chromatin in BLM-treated cells (diameter, 20–25 µm) is normalized to ~12 µm after co-incubation of the cells with BLM and polyP. A sequential application of the drugs (BLM for 3 days, followed by an exposure to polyP) does not cause this normalization. During co-incubation of BLM with polyP the gene for the BLM hydrolase is upregulated. It is concluded that by upregulating this enzyme polyP prevents the toxic side effects of BLM. These data might also contribute to an application of BLM in COVID-19 patients, since polyP inhibits binding of SARS-CoV-2 to cellular ACE2.

scholarly journals The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
E. Cil ◽  
A. M. Isac ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Human Lung ◽  
Cell Types ◽  
Receptor Activation ◽  
Surface Proteins ◽  
Mouse Lung ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Cellular Entry ◽  
Experimental Data Analysis

AbstractSARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals TiO2 nanoparticles generate superoxide and alter gene expression in human lung cells

RSC Advances ◽  
2019 ◽  
Vol 9 (43) ◽  
pp. 25039-25047 ◽  
Author(s):  
Dhanya T. Jayaram ◽  
Ashwath Kumar ◽  
Linda E. Kippner ◽  
Po-Yi Ho ◽  
Melissa L. Kemp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fluorescence Microscopy ◽  
Tio2 Nanoparticles ◽  
Human Lung ◽  
Lung Cells ◽  
Rna Seq ◽  
Nanoparticle Exposure ◽  
Human Lung Cells

Human lung cells have a multi-generational response to TiO2 nanoparticle exposure determined by RNA-Seq and fluorescence microscopy.

Potential Markers of Cisplatin Treatment Response Unveiled by NMR Metabolomics of Human Lung Cells

2013 ◽  
Vol 10 (11) ◽  
pp. 4242-4251 ◽  
Author(s):  
I. F. Duarte ◽  
A. F. Ladeirinha ◽  
I. Lamego ◽  
A. M. Gil ◽  
L. Carvalho ◽  
...  
Keyword(s):  
Treatment Response ◽  
Human Lung ◽  
Lung Cells ◽  
Nmr Metabolomics ◽  
Human Lung Cells
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