Chapter 17:DNA Topoisomerases as Promising Targets for Leishmania Chemotherapy

DNA topoisomerases (Top) have been identified as promising targets for therapeutic intervention in leishmaniasis. Leishmania parasites have a complete set of six classes of Top enzymes that operate in solving topological problems generated during DNA replication, transcription and recombination, in the nucleus and in the single mitochondrion. Unlike most TopIBs, the Leishmania enzyme is a heterodimeric (AB) complex with poor homology with that of the host, thereby providing a highly selective therapeutic target for drug discovery. The set of Top type IA enzymes of Leishmania includes a true mitochondrial Top type IA and additional Top type IIIα and Top type IIIβ proteins with exclusive decatenase, rather than relaxase, activity. Top type II enzymes, both nuclear and mitochondrial, carry out strand passage through a double-strand break, including decatenating and unknotting activities, and are key enzymes involved in kinetoplast DNA (kDNA) replication. Due to these differences, many compounds clinically tested as Top type IB and Top type II inhibitors in cancer and antibacterial processes, have been evaluated for repurposing as drugs against Leishmania. As such, camptothecin derivatives, indenoisoquinolines, indeno 1,5-naphthyridines and both acetylenic and alkynoic fatty acids are preferential inhibitors of Leishmania Top type IB. For their part, fluoroquinolones, anthracyclines and podophyllotoxins are renowned inhibitors of Top type II, and good correlations have been reported between their anti-leishmanial effect and Top type II inhibition. In the current chapter we update the structure and function of Leishmania topoisomerases, highlighting the importance of these enzymes as targets for drug discovery.