Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany.
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland.
ACS Infect Dis. 2024 May 10;10(5):1664-1678. doi: 10.1021/acsinfecdis.4c00020. Epub 2024 Apr 30.
In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm and its target protease cathepsin B1 (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 newly transformed schistosomula (NTS), adult worms, and CB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs "CB1" approach) demonstrated improved efficacy against NTS and adult worms, with from the "CB1" approach emerging as the most potent compound. displayed nanomolar inhibition of CB1 ( = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound toward 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.
在这项研究中，我们从内部筛选中确定并优化了两个先导结构，它们对寄生扁形虫和其靶标蛋白酶组织蛋白酶 B1（CB1）具有良好的抑制效果。我们的相关性分析强调了化合物的物理化学性质对其体外活性的重要性，这导致了优化先导结构的双重方法，既考虑了新转化的尾蚴（NTS）、成虫中的表型效应，也考虑了对 CB1 的抑制作用。两种方法（“表型”与“CB1”方法）优化的化合物均显示出对 NTS 和成虫的疗效提高，其中“CB1”方法的化合物 表现出最强的活性。 对 CB1 具有纳摩尔抑制作用（ = 0.050 μM），同时对人源靶标组织蛋白酶保持选择性。此外，化合物 对成虫的疗效大大提高（在 10 μM 时 86%的死虫，在 1 μM 时 68%，在 0.1 μM 时 35%），表明其作为一种新的抗血吸虫病治疗药物具有潜力，其渗透性得到了改善。
