Mode of action of Curaxin-137

Abstract

Infection with the protozoan parasite, Trypanosoma brucei, causes a fatal illness known as human African trypanosomiasis (HAT). Drugs necessary to treat HAT have severe limitations including administration by injection, toxic side effects and emerging drug resistance. Using an alternative use drug discovery approach, we tested the effects of Curaxins, compounds originally designed for cancer chemotherapy, on T. brucei. Focused screening in vitro demonstrated that Curaxins inhibit T. brucei population growth at nanomolar concentrations. Curaxin-137 (CBL0137) cured trypanosome-infected mice in an animal model of acute HAT. In “mode of action” studies, CBL0137 inhibited synthesis of kinetoplast (mitochondrial) DNA and nuclear DNA. Consequently, CBL0137-treated trypanosomes failed to increase their total DNA content (from 2C to 4C). Furthermore, CBL0137 blocked mitosis. Therefore, CBL0137 caused both G1 and S-phase arrests in T. brucei and inhibited mitosis. In conclusion, the work presented in this dissertation establishes Curaxin-137 as a lead drug against T. brucei whose mode of action affects replication of the parasite’s mitochondrial and nuclear DNA.