In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors
Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 an...
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2024-09-01
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| author | Sara Maluck Rivka Bobrovsky Miklós Poór Roman W. Lange Torsten Steinmetzer Ákos Jerzsele András Adorján Dávid Bajusz Anita Rácz Erzsébet Pászti-Gere |
| author_facet | Sara Maluck Rivka Bobrovsky Miklós Poór Roman W. Lange Torsten Steinmetzer Ákos Jerzsele András Adorján Dávid Bajusz Anita Rácz Erzsébet Pászti-Gere |
| author_sort | Sara Maluck |
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| description | Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α<sub>1</sub>-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4. |
| format | Article |
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| language | English |
| publishDate | 2024-09-01 |
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| series | Biomedicines |
| spelling | doaj-art-c3d87a5f787f41938ffa7fcfd80fda1e2025-08-20T01:56:10ZengMDPI AGBiomedicines2227-90592024-09-01129207510.3390/biomedicines12092075In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin InhibitorsSara Maluck0Rivka Bobrovsky1Miklós Poór2Roman W. Lange3Torsten Steinmetzer4Ákos Jerzsele5András Adorján6Dávid Bajusz7Anita Rácz8Erzsébet Pászti-Gere9Department of Pharmacology and Toxicology, University of Veterinary Medicine, Hungary István utca 2, H-1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, Hungary István utca 2, H-1078 Budapest, HungaryDepartment of Laboratory Medicine, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, HungaryDepartment of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, GermanyDepartment of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, GermanyDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, Hungary István utca 2, H-1078 Budapest, HungaryDepartment of Microbiology and Infectious Diseases, University of Veterinary Medicine, Hungária krt. 23-25, H-1143 Budapest, HungaryMedicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryPlasma Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, Hungary István utca 2, H-1078 Budapest, HungaryInhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α<sub>1</sub>-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4.https://www.mdpi.com/2227-9059/12/9/2075furin inhibitorsprotein bindingoxidative stressporcine intestinal cellshepatocytescytochrome P450 3A4 |
| spellingShingle | Sara Maluck Rivka Bobrovsky Miklós Poór Roman W. Lange Torsten Steinmetzer Ákos Jerzsele András Adorján Dávid Bajusz Anita Rácz Erzsébet Pászti-Gere In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors Biomedicines furin inhibitors protein binding oxidative stress porcine intestinal cells hepatocytes cytochrome P450 3A4 |
| title | In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors |
| title_full | In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors |
| title_fullStr | In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors |
| title_full_unstemmed | In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors |
| title_short | In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors |
| title_sort | in vitro evaluation of antipseudomonal activity and safety profile of peptidomimetic furin inhibitors |
| topic | furin inhibitors protein binding oxidative stress porcine intestinal cells hepatocytes cytochrome P450 3A4 |
| url | https://www.mdpi.com/2227-9059/12/9/2075 |
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