Graphene quantum dots harvest anti-trypanosomatid efficacy by disrupting antioxidant networks centered on trypanothione reductase

Abstract Background Trypanosomiasis is a highly lethal infectious disease caused by trypanosome, leading to a severe social and economic burden worldwide. Due to the lack of mechanism research, application of the promising nanomaterials and nanotechnologies in treatment of trypanosomiasis is limited. Results Herein, the toxicological effects induced by graphene quantum dots (GQDs) on T. brucei and the underlying mechanism are investigated. First, the biological/cytotoxic effects are evaluated, including endotytosis, cell viability, apoptosis, ROS production and morphological defects of subcellular organelles. Considering the few experimentally-determined 3D structures of T. brucei proteins, next, a computed structure database of T. brucei genome-wide proteins is constructed from I-TASSER, AlphaFold2 and MD simulation. Then, the database is used for docking with GQDs, and two goups of potential target proteins with transporter activity and antioxidant activity are screened out. Last, TryR stands out as a vital target due to its high binding energy with GQDs at active site and its key role in the trypanothione-dependent antioxidant network of T. brucei , which is further verified by theoretical (MD simulation) and experimental (BLI, inhibition of enzyme activity) means. Conclusions Evidences from this study suggest that GQD-induced cytotoxicity on T. brucei results from interference of GQDs with the lineage-specific antioxidant network with TryR as a key target. These findings provide theoretical insights into the rational design of nanomedical materials for trypanosomiasis.