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1.
Pharmaceuticals (Basel) ; 15(9)2022 Aug 31.
Article in English | MEDLINE | ID: covidwho-2058911

ABSTRACT

We characterized the in vitro safety and bioavailability profile of silvestrol, a compound effective against various viruses, such as corona- and Ebolaviruses, with an EC50 value of about 5 nM. The cytotoxic profile of silvestrol was assessed in various cancer cell lines, as well as the mutagenic and genotoxic potential with Ames and micronuclei tests, respectively. To identify off-target effects, we investigated whether silvestrol modulates G-protein coupled receptor (GPCR) signaling pathways. To predict the bioavailability of silvestrol, its stability, permeability and cellular uptake were determined. Silvestrol reduced viability in a cell-type-dependent manner, mediated no off-target effects via GPCRs, had no mutagenic potential and minor genotoxic effects at 50 nM. Silvestrol did not disturb cell barrier integrity, showed low membrane permeability, was stable in liver microsomes and exhibited good cellular uptake. Efficient cellular uptake and increased cytotoxicity were observed in cell lines with a low expression level of the transport protein P-glycoprotein, the known efflux transporter of silvestrol. In conclusion, silvestrol showed low permeability but good cellular uptake and high stability. Cell-type-dependent cytotoxicity seems to be caused by the accumulation of silvestrol in cells lacking the ability to expel silvestrol due to low P-glycoprotein levels.

2.
Viruses ; 14(3)2022 03 03.
Article in English | MEDLINE | ID: covidwho-1732235

ABSTRACT

Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5'-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5'-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.


Subject(s)
Antineoplastic Agents , Coronavirus , 5' Untranslated Regions , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Constriction , Humans
3.
Int J Mol Sci ; 23(3)2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1625123

ABSTRACT

SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications-including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)-have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.


Subject(s)
Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/genetics , Acetaminophen/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Caco-2 Cells , Disease Progression , Enzyme Activation/drug effects , Etoricoxib/pharmacology , Flurbiprofen/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Humans , Ibuprofen/pharmacology , Male , Mice , Mice, Inbred C57BL , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Internalization/drug effects
4.
Life (Basel) ; 11(8)2021 Aug 10.
Article in English | MEDLINE | ID: covidwho-1399330

ABSTRACT

Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin-renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). METHODS: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. RESULTS: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. CONCLUSION: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.

5.
J Cell Mol Med ; 24(12): 6988-6999, 2020 06.
Article in English | MEDLINE | ID: covidwho-186413

ABSTRACT

Outbreaks of infections with viruses like Sars-CoV-2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona-, Ebola-, Zika-, Picorna-, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down-regulated several pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, CCL2, CCL18) and increased TNF-α during differentiation and activation of M1-macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti-inflammatory potential of M2-macrophages by increasing expression of anti-inflammatory surface markers CD206, TREM2 and reducing release of pro-inflammatory IL-8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down-regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cytokines/genetics , Dendritic Cells/drug effects , Immunologic Factors/pharmacology , Macrophages/drug effects , Triterpenes/pharmacology , Betacoronavirus/growth & development , Betacoronavirus/immunology , Cell Differentiation/drug effects , Chikungunya virus/drug effects , Chikungunya virus/growth & development , Chikungunya virus/immunology , Cytokines/classification , Cytokines/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , Ebolavirus/drug effects , Ebolavirus/growth & development , Ebolavirus/immunology , Gene Expression Profiling , Gene Expression Regulation/drug effects , Hepatitis E virus/drug effects , Hepatitis E virus/growth & development , Hepatitis E virus/immunology , Humans , Immunity, Innate/drug effects , Macrophages/immunology , Macrophages/virology , Organ Specificity , Picornaviridae/drug effects , Picornaviridae/growth & development , Picornaviridae/immunology , Primary Cell Culture , SARS-CoV-2 , Signal Transduction , Zika Virus/drug effects , Zika Virus/growth & development , Zika Virus/immunology
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