Structural studies of mitochondrial topoisomerase II from trypanosomatids

Abstract

Neglected tropical diseases affect the lives of one-sixth of the world population, being characteristic of the poorest populations. They are seventeen infectious diseases caused by various pathogens such as bacteria, worms, helminths and protozoa. Those caused by trypanosomatid protozoa, such as African trypanosomiasis (sleeping sickness), leishmaniasis and American trypanosomiasis (Chagas disease) are highly prevalent and impacting. The drugs currently used to treat these diseases have severe side effects and resistance cases are reported, which makes the selection of new molecular targets and the development of innovative chemotherapeutic agents extremely important. Topoisomerases are enzymes involved in regulation of DNA supercoiling and overcoming topological barriers during replication, transcription, recombination and repair. The type II topoisomerases are essential for trypanosomes since, in addition to their role in nuclear DNA metabolism, these enzymes might also play an important role in the replication and organization of DNA contained in a specialized region called kinetoplast. DNA topoisomerases are described as chemotherapeutic targets for bacteria (quinolones) and cancer (camptothecin). The topoisomerase II gene was identified in the following kinetoplastidas: Crithidia fasciculata, Leishmania donovani, L. infantum, L. chagasi, Trypanosoma brucei, T. cruzi and Bodo saltans. In relation to the homologous human protein, there is low conservation, with 30-35% identity and 45-65% similarity, which makes it an attractive molecular target. This research project aims to elucidate the three-dimensional structure of the mitochondrial topoisomerase II from trypanosomatid, shedding light on the elucidation of molecular features of the binding of known inhibitors and the search for new selective inhibitors. (AU)