ABSTRACT
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 (SmCB1). 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 SmCB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs "SmCB1" approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the "SmCB1" approach emerging as the most potent compound. 2h displayed nanomolar inhibition of SmCB1 (Ki = 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.
Subject(s)
Cathepsin B , Schistosoma mansoni , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , Schistosoma mansoni/genetics , Animals , Cathepsin B/antagonists & inhibitors , Cathepsin B/metabolism , Schistosomiasis mansoni/drug therapy , Drug Design , Humans , Phenotype , Structure-Activity Relationship , Anthelmintics/pharmacology , Anthelmintics/chemistry , Helminth Proteins/antagonists & inhibitorsABSTRACT
Hardly any new tracers attracted more attention in nuclear medicine in the last couple of years than radiolabeled fibroblast activation protein inhibitors (FAPi's). Molecules targeting cancer-associated fibroblasts (CAFs) or disease-associated fibroblasts in benign disorders (DAFs) gave rise to a new class of radiopharmaceuticals widely applicable for imaging and with the desired use as therapeutic compounds. Despite displaying benefits in diagnostic sensitivity over FDG, most FAP-targeting compounds in today's clinical routine continue to lack therapeutic utility due to short tumor retention. In this study, we evaluated 3BP-3940, specifically designed for achieving prolonged tumor retention and remarkably low uptake in healthy tissues. We herein present the automated manufacturing of gallium-68 (Ga-68) and lutetium-177 (Lu-177)-labeled 3BP-3940, their respective in vitro stability, validation of an automated production process, and validation of an analytical HPLC method for quality control. Finally, we give a first insight into the clinical utility of the two compounds.
