Temporal and Wash-Out Studies Identify Medicines for Malaria Venture Pathogen Box Compounds with Fast-Acting Activity against Both Trypanosoma cruzi and Trypanosoma brucei.

Abstract

Chagas disease caused by the protozoan Trypanosoma cruzi is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the Trypanosoma brucei sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages; thus, there is a need to find improved treatments. To identify new molecules for the drug discovery pipelines for these diseases, we have utilised in vitro assays to identify compounds with selective activity against both T. cruzi and T.b. brucei from the Medicines for Malaria Venture (MMV) Pathogen Box compound collection. To prioritise these molecules for further investigation, temporal and wash off assays were utilised to identify the speed of action and cidality of compounds. For translational relevance, compounds were tested against clinically relevant T.b. brucei subspecies. Compounds with activity against T. cruzi cytochrome P450 (TcCYP51) have not previously been successful in clinical trials for chronic Chagas disease; thus, to deprioritise compounds with this activity, they were tested against recombinant TcCYP51. Compounds with biological profiles warranting progression offer important tools for drug and target development against kinetoplastids.