Identification of Prazosin as a Potential Flagellum Attachment Zone 1(FAZ1) Inhibitor for the Treatment of Human African Trypanosomiasis

Human African trypanosomiasis (HAT) remains a health threat to sub-Saharan Africa. The current treatments suffer from drug resistance and life-threatening side effects, making drug discovery for HAT still important. A high-throughput screening of the library of pharmaceutically active compounds identified prazosin, an α-adrenoceptor antagonist, that showed selective activity toward Trypanosoma brucei brucei. Furthermore, a series of prazosin analogues were examined, and overall, the new analogues had improved activity and selectivity. To elucidate the binding partner, a biotin-conjugated probe was synthesized, and a protein pulldown assay combined with a proteomic analysis identified the flagellum attachment zone 1 (FAZ1) filament as an interacting partner. Additionally, prazosin treatment resulted in dysfunction of the flagellum of trypanosome cells, which is indicative of a FAZ1 irregularity. We also examined the drug distribution by utilizing immunofluorescence with a designed fluorescent analogue that showed partial colocalization with FAZ1. With the activity of the prazosin analogues, a structure-activity relationship (SAR) was summarized for future lead optimization. Our findings provide a new group of FAZ1 inhibitors as novel antitrypanosomal agents.