Sessions

The proprotein convertase furin is of increasing interest as a therapeutic target, due to its role in the cleavage of certain bacterial toxins and viral surface proteins. Based on the increasing prevalence of antibiotic-resistant bacteria, such as Pseudomonas aeruginosa, there is an urgent need to develop new antimicrobial strategies, with furin inhibition being a promising approach. In the present study, the furin inhibitors MI-1851 and MI-2415 were evaluated based on their antipseudomonal activity and their safety profiles. A significant antipseudomonal effect was detectable at a concentration of only 0.5 µM in case of MI-1851, and MI-2415 also showed protective effects in a Madin-Darby canine kidney cell model against the bacteria, but in a bit higher concentration (25 µM). Our findings also confirmed that neither inhibitor induced significant cytotoxicity (CCK-8 assay) and that both have negligible effects on the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status up to 100 µM in IPEC-J2 cells. The effect of MI-2415 has been assessed in the same assays on primary human hepatocytes at up to 100 µM, with no significant impact on cell viability or reactive oxygen species formation. The data further indicate that MI-2415 did not form detectable complexes with human serum albumin. MI-1851 and MI-2415 exhibited concentration-dependent cytochrome P450 (CYP) 3A4 activity inhibition in a human hepatic microsomal approach at high doses. The furin inhibitor MI-2415 has also been evaluated in hepatocytes and induced significant blockage only at 100 µM. Despite these inhibitory effects on CYP3A4, both furin inhibitors, MI-1851 and MI-2415, displayed a good safety profile in vitro and demonstrated antipseudomonal therapeutic activity, thus rendering them promising drug candidates for further development as antimicrobial agents.