In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors
"> Figure 1
<p>Chemical structures of the used furin inhibitors MI-1851 (<b>left</b> structure) [<a href="#B21-biomedicines-12-02075" class="html-bibr">21</a>] and MI-2415 (<b>right</b> structure) [<a href="#B22-biomedicines-12-02075" class="html-bibr">22</a>].</p> "> Figure 2
<p>Effects of MI-1851 and MI-2415 on the fluorescence emission signals of HSA and AGP. Representative emission spectra ((<b>A</b>); λ<sub>ex</sub> = 295 nm) and emission intensities ((<b>B</b>); λ<sub>ex</sub> = 295 nm, λ<sub>em</sub> = 340 nm; n = 3) of HSA (2 μM) in the absence and in the presence of increasing levels of inhibitor MI-2415 (1, 2, 3, 4, 7, and 10 μM) in PBS (pH 7.4). As it has been reported, also inhibitor MI-1851 did not affect the emission signal of HSA in the same experimental model (see in panel (<b>B</b>) with red dashed line) [<a href="#B12-biomedicines-12-02075" class="html-bibr">12</a>]. Representative emission spectra of AGP (2 μM) in the absence and in the presence of increasing concentrations (0.25, 0.5, 1, 1.5, 2, and 2.5 μM) of compounds MI-1851 (<b>C</b>) and MI-2415 (<b>D</b>) in PBS (pH 7.4; λ<sub>ex</sub> = 285 nm). Influence of inhibitors MI-1851 and MI-2415 (means ± SEM) on the emission intensity of AGP ((<b>E</b>); λ<sub>ex</sub> = 285 nm, λ<sub>em</sub> = 337 nm; n = 3).</p> "> Figure 3
<p>Determination of <span class="html-italic">Pseudomonas aeruginosa</span> (Ps aer) effect (10<sup>6</sup> CFU/mL) on cell viability in MDCK cells with and without inhibitor MI-1851 (<b>A</b>) and MI-2415 (<b>B</b>) at different concentrations (0.5, 1, 2.5, 5, 10, 25, 50, and 100 µM). Furin inhibitors were added 2 h prior to and continuously during 5 h bacterial incubation. The data are the mean cell viability values expressed in percentage of control (%) ± standard errors of mean (SEM) (*** <span class="html-italic">p</span> < 0.001, <span class="html-italic">p</span> > 0.05; n = 4–8).</p> "> Figure 4
<p>Cell viability after a 24 h treatment of IPEC-J2 cells with furin inhibitors MI-1851 or MI-2415 at 50 µM and 100 µM. The cell viability values are presented as percentage of control (%) ± standard errors of mean (SEM). Each group contained n = 3–4 samples (<span class="html-italic">p</span> > 0.05).</p> "> Figure 5
<p>Effect of inhibitors MI-1851 and MI-2415 on extracellular H<sub>2</sub>O<sub>2</sub> production. Both inhibitors were added at concentrations of 50 or 100 μM for 24 h on IPEC-J2 cells. Data represent the mean extracellular H<sub>2</sub>O<sub>2</sub> (%) expressed in control ± standard errors of mean (SEM) by using the fluorescence readings (<span class="html-italic">p</span> > 0.05; n = 4).</p> "> Figure 6
<p>Effects of inhibitors MI-1851 and MI-2415 at different concentrations (50 and 100 μM) on intracellular oxidative stress on IPEC-J2 cells. The data represent the mean intracellular ROS (%) expressed in control ± standard errors of mean (SEM) (<span class="html-italic">p</span> > 0.05; n = 4).</p> "> Figure 7
<p>Effects of inhibitor MI-2415 at different concentrations (50 and 100 μM) on cell viability ((<b>A</b>), CCK-8), extracellular ((<b>B</b>), Amplex Red) and intracellular ((<b>C</b>), DCFH-DA) oxidative stress, and on CYP3A4 activity (<b>D</b>) in PHHs compared to control. The data represent the mean measured values (%) expressed in percentage of control ± standard errors of mean (SEM) (*** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, <span class="html-italic">p</span> > 0.05; n = 3–6). Ketoconazole (KCZ) at 10 µM was used as reference CYP3A4 inhibitor.</p> "> Figure 8
<p>Effects of inhibitors MI-1851 and MI-2415 at concentrations of 25, 50, and 100 µM on microsomal CYP3A4 function. The data represent the mean CYP3A4 activity (%) expressed in percentage of control ± standard errors of mean (SEM) (*** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, <span class="html-italic">p</span> > 0.05; n = 3). Ketoconazole (KCZ) at 10 µM was used as reference CYP3A4 inhibitor.</p> "> Figure 9
<p>Predicted binding modes for MI-1851 (<b>A</b>) and MI-2415 (<b>B</b>) in the active site of CYP3A4. While the site is big enough to fit the ligands, the cluster of positively charged arginine residues (red spheres) produces a repulsive force against the positively charged groups of the ligands (green spheres). The canavanine groups (grey spheres) have a pKa value close to 7, meaning that they can be present in the protonated and deprotonated forms as well. This explains the intermediate level of CYP3A4 inhibition, as the most heavily charged (+4) protomers are unlikely to bind, while the mildly charged forms (+2) are easily accommodated.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Spectroscopic Studies on Protein Binding of Furin Inhibitors
2.2. MDCK Cell Culturing and Pseudomonas aeruginosa Experiments
2.3. IPEC-J2 and PHH Cell Culturing
2.4. Cytotoxicity Measurements in IPEC-J2 and PHH-Based Cell Models
2.5. Amplex Red Measurements
2.6. DCFH2-DA ROS Measurements
2.7. CYP3A4 Activity Measurement and Modelling of Its Interaction with Furin Inhibitors
2.8. Statistical Analysis
3. Results
3.1. Interactions of Inhibitors MI-1851 and MI-2415 with HSA and AGP
3.2. Antipseudomonal Effect of Inhibititors MI-1851 and MI-2415
3.3. Cytotoxicity Investigations in IPEC-J2 Cells
3.4. Peroxide Production in IPEC-J2 Cells
3.5. DCFH-DA Assay to Detect Peroxide Production in IPEC-J2 Cells
3.6. Viability and Redox Status of Hepatocytes Exposed to Inhibitor MI-2415
3.7. Microsomal CYP3A4 Activity Assay
3.8. Molecular Modelling of MI-1851 and MI-2415 with CYP3A4
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
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Maluck, S.; Bobrovsky, R.; Poór, M.; Lange, R.W.; Steinmetzer, T.; Jerzsele, Á.; Adorján, A.; Bajusz, D.; Rácz, A.; Pászti-Gere, E. In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors. Biomedicines 2024, 12, 2075. https://doi.org/10.3390/biomedicines12092075
Maluck S, Bobrovsky R, Poór M, Lange RW, Steinmetzer T, Jerzsele Á, Adorján A, Bajusz D, Rácz A, Pászti-Gere E. In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors. Biomedicines. 2024; 12(9):2075. https://doi.org/10.3390/biomedicines12092075
Chicago/Turabian StyleMaluck, Sara, Rivka Bobrovsky, Miklós Poór, Roman W. Lange, Torsten Steinmetzer, Ákos Jerzsele, András Adorján, Dávid Bajusz, Anita Rácz, and Erzsébet Pászti-Gere. 2024. "In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors" Biomedicines 12, no. 9: 2075. https://doi.org/10.3390/biomedicines12092075