| Autor: |
Fuchs N; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Zimmermann RA; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Schwickert M; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Gunkel A; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Zimmer C; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Meta M; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Schwickert K; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Keiser J; Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland., Haeberli C; Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland., Kiefer W; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany., Schirmeister T; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany. |
| Abstrakt: |
In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm Schistosoma mansoni and its target protease S. mansoni cathepsin B1 ( Sm CB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds' in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in S. mansoni newly transformed schistosomula (NTS), adult worms, and Sm CB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs " Sm CB1" approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the " Sm CB1" approach emerging as the most potent compound. 2h displayed nanomolar inhibition of Sm CB1 ( K i = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound 2h toward S. mansoni adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability. |
