scholarly journals Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties

2021 ◽  
Vol 12 (38) ◽  
pp. 12600-12609
Author(s):  
Tim Hempel ◽  
Katarina Elez ◽  
Nadine Krüger ◽  
Lluís Raich ◽  
Jonathan H. Shrimp ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Viral Entry ◽  
Clinical Assessment ◽  
Human Lung ◽  
Cell Entry ◽  
Lung Cells ◽  
Host Proteins ◽  
Synergistic Inhibition ◽  
Human Lung Cells

SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host proteins for viral entry into human lung cells and is blocked by otamixaban in combination with a covalent protease inhibitor.

scholarly journals IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

2020 ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Jana Krüger ◽  
Sandra Heller ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

scholarly journals Enzalutamide, a prostate cancer therapeutic, downregulates TMPRSS2 in lung and reduces cellular entry of SARS-CoV-2

2021 ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
A. M. Isac ◽  
L. L. Yates ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Viral Entry ◽  
Human Lung ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation

Abstract The COVID-19 pandemic, caused by the novel human coronavirus SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells 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; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the 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. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. To determine therapeutic potential, we assessed uptake of SARS-CoV-2 Spike protein pseudotyped lentivirus and live SARS-CoV-2 into human lung cells and saw a significant reduction in viral entry and infection upon treatment with the antiandrogens enzalutamide and bicalutamide. In support of this new experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types that are 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.

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

2021 ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Jana Krüger ◽  
Sandra Heller ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

Abstract Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

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.

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