Folates in Trypanosoma brucei: Achievements and Opportunities

Trypanosoma brucei is the agent of human African trypanosomiasis (HAT), a neglected disease that threatens the lives of 65 million people in sub‐Saharan Africa every year. Unfortunately, available therapies are unsatisfactory, due primarily to safety issues and development of drug resistance. Over the last decades significant effort has been made in the discovery of new potential anti‐HAT agents, with help from the World Health Organization (WHO) and private–public partnerships such as the Drugs for Neglected Diseases Initiative (DNDi). Whereas antifolates have been a valuable source of drugs against bacterial infections and malaria, compounds effective against T. brucei have not yet been identified. Considering the relatively simple folate metabolic pathway in T. brucei, along with results obtained in this research field so far, we believe that further investigations might lead to effective chemotherapeutic agents. Herein we present a selection of the more promising results obtained so far in this field, underlining the opportunities that could lead to successful therapeutic approaches in the future. Taking aim at HAT: Targeting the folate pathway has been a valuable strategy for the treatment of various diseases, particularly microbial infections. Despite the simple metabolism of folates in Trypanosoma brucei, no effective antifolate to treat T. brucei infections has yet been described. In this minireview, we analyze the folate pathway of this parasite, highlighting a selection of the most important results obtained to date in this research field.