title: Nelfinavir and lopinavir impair Trypanosoma cruzi trypomastigote infection in mammalian host cells and show anti-amastigote activity.
abstract: There is an urgent need to implement new strategies and to search for new chemotherapeutic targets to combat Chagas' disease. In this context, repositioning of clinically approved drugs appears as a viable tool to combat this and several other neglected pathologies. An example is the use of aspartic peptidase inhibitors (PIs) currently applied in human immunodeficiency virus (HIV) treatment against different infectious agents. Therefore, the main objective of this work was to verify the effects of the HIV-PIs nelfinavir and lopinavir against Trypanosoma cruzi using in vitro models of infection. Cytotoxicity assays with LLC-MK2epithelial cells and RAW macrophages allowed an evaluation of the effects of HIV-PIs on the interaction between trypomastigotes and these cells as well as the survival of intracellular amastigotes. Pre-treatment of trypomastigotes with nelfinavir and lopinavir inhibited the association index with LLC-MK2cells and RAW macrophages in a dose- and time-dependent manner. In addition, nelfinavir and lopinavir also significantly reduced the number of intracellular amastigotes in both mammalian cell lineages, particularly when administered in daily doses. Both compounds had no effect on nitric oxide production in infected RAW macrophages. These results open the possibility for the use of HIV-PIs as a tangible alternative in the treatment of Chagas' disease. However, the main mechanism of action of nelfinavir and lopinavir has yet to be elucidated, and more studies using in vivo models must be conducted.
authors.affiliation: Departamento de Microbiologia Geral, Laboratório de Investigação de Peptidases, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
authors.forename: Leandro S
authors.initials: LS
authors.lastname: Sangenito
authors.affiliation: Laboratório de Estudos Integrados em Protozoologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: d'Avila-Levy
authors.affiliation: Departamento de Microbiologia Geral, Laboratório de Investigação de Peptidases, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil. Electronic address: mbranquinha@micro.ufrj.br.
authors.forename: Marta H
authors.initials: MH
authors.lastname: Branquinha
authors.affiliation: Departamento de Microbiologia Geral, Laboratório de Investigação de Peptidases, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Programa de Pós-Graduação em Bioquímica, Instituto de Química, UFRJ, Rio de Janeiro, Brazil. Electronic address: andre@micro.ufrj.br.
authors.forename: André L S
authors.initials: ALS
authors.lastname: Santos
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000469:parasitology; D058492:Drug Repositioning; D061466:Lopinavir / Q000494:pharmacology*; D008253:Macaca mulatta; D051379:Mice; D019888:Nelfinavir / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D061466:Lopinavir; D057055:Aspartic Acid Proteases; D019888:Nelfinavir
keywords: Amastigotes; Cellular interaction; HIV-PI; Lopinavir; Nelfinavir; Trypanosoma cruzi