title: Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery.
abstract: The Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top) are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking-closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid's Tops, their new structural features, their involvement both in the physiology and virulence of these parasites, as well as their use as promising targets for drug discovery.
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Balaña-Fouce
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alvarez-Velilla
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fernández-Prada
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Estrada
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Reguera
keywords: CL, cutaneous leishmaniasis; Chemotherapy; DALYs, disability-adjusted life years; DNA topology; Kinetoplastids; NGO, non-governmental organization; NLS, Nuclear Localization Signal; NTD, neglected tropical diseases; Target-based drug discovery; Top, DNA topoisomerase; Topoisomerases; Tritryps; VL, visceral leishmaniasis; kDNA, kinetoplast DNA; lk, linking number