title: Indotecan (LMP400) and AM13-55: two novel indenoisoquinolines show potential for treating visceral leishmaniasis.
abstract: Visceral leishmaniasis is an emerging neglected tropical disease (NTD) caused by the protozoan Leishmania infantum in the countries bordering the Mediterranean Basin. Currently there is no effective vaccine against this disease, and the therapeutic approach is based on toxic derivatives of Sb(V). Therefore, the discovery of new therapeutic targets and the development of drugs designed to inhibit them comprise an extremely important approach to fighting this disease. DNA topoisomerases (Top) have been identified as promising targets for therapy against leishmaniasis. These enzymes are involved in solving topological problems generated during replication, transcription, and recombination of DNA. Being unlike that of the mammalian host, type IB DNA topoisomerase (TopIB) from Leishmania spp. is a unique bisubunit protein, which makes it very interesting as a selective drug target. In the present investigation, we studied the effect of two TopIB poisons with indenoisoquinoline structure, indotecan and AM13-55, on a murine BALB/c model of infected splenocytes with L. infantum, comparing their effectiveness with that of the clinically tested leishmanicidal drug paromomycin. Both compounds have high selectivity indexes compared with uninfected splenocytes. SDS-KCl-precipitable DNA-protein complexes in Leishmania promastigotes and in vitro cleaving assays confirmed that these drugs are Top poisons. The inhibitory potency of both indenoisoquinolines on L. infantum recombinant TopIB was assessed in vitro, with results showing that indotecan was the most active compound, preventing the relaxation of supercoiled DNA. Experimental infections in susceptible BALB/c mice treated with 2.5 mg/kg body weight/day once every other day for a total of 15 days showed that indotecan cleared more than 80% of the parasite burden of the spleen and liver, indicating promising activity against visceral leishmaniasis.
authors: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana, León, Spain.
authors: Rafael
authors: R
authors: Balaña-Fouce
authors: Christopher F
authors: CF
authors: Prada
authors: José María
authors: JM
authors: Requena
authors: Mark
authors: M
authors: Cushman
authors: Yves
authors: Y
authors: Pommier
authors: Raquel
authors: R
authors: Álvarez-Velilla
authors: José Miguel
authors: JM
authors: Escudero-Martínez
authors: Estefania
authors: E
authors: Calvo-Álvarez
authors: Yolanda
authors: Y
authors: Pérez-Pertejo
authors: Rosa M
authors: RM
authors: Reguera
mesh_terms: D000818:Animals; D005260:Female; D018314:Leishmania infantum / Q000187:drug effects / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000469:parasitology; D014344:Trypanocidal Agents / Q000627:therapeutic use*
chemical_list: D014344:Trypanocidal Agents