title: Epoxy-α-lapachone has in vitro and in vivo anti-leishmania (Leishmania) amazonensis effects and inhibits serine proteinase activity in this parasite.
abstract: Leishmania (Leishmania) amazonensis is a protozoan that causes infections with a broad spectrum of clinical manifestations. The currently available chemotherapeutic treatments present many problems, such as several adverse side effects and the development of resistant strains. Natural compounds have been investigated as potential antileishmanial agents, and the effects of epoxy-α-lapachone on L. (L.) amazonensis were analyzed in the present study. This compound was able to cause measurable effects on promastigote and amastigote forms of the parasite, affecting plasma membrane organization and leading to death after 3 h of exposure. This compound also had an effect in experimentally infected BALB/c mice, causing reductions in paw lesions 6 weeks after treatment with 0.44 mM epoxy-α-lapachone (mean lesion area, 24.9 ± 2.0 mm(2)), compared to untreated animals (mean lesion area, 30.8 ± 2.6 mm(2)) or animals treated with Glucantime (mean lesion area, 28.3 ± 1.5 mm(2)). In addition, the effects of this compound on the serine proteinase activities of the parasite were evaluated. Serine proteinase-enriched fractions were extracted from both promastigotes and amastigotes and were shown to act on specific serine proteinase substrates and to be sensitive to classic serine proteinase inhibitors (phenylmethylsulfonyl fluoride, aprotinin, and antipain). These fractions were also affected by epoxy-α-lapachone. Furthermore, in silico simulations indicated that epoxy-α-lapachone can bind to oligopeptidase B (OPB) of L. (L.) amazonensis, a serine proteinase, in a manner similar to that of antipain, interacting with an S1 binding site. This evidence suggests that OPB may be a potential target for epoxy-α-lapachone and, as such, may be related to the compound's effects on the parasite.
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, Brazil.
authors.forename: Franklin
authors.initials: F
authors.lastname: Souza-Silva
authors.affiliation: Universidade Federal Fluminense, Instituto de Biologia, Pós-Graduação em Ciências e Biotecnologia, Niterói, Brazil.
authors.forename: Saulo Cabral
authors.initials: SC
authors.lastname: Bourguignon
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, Brazil.
authors.forename: Bernardo Acácio Santini
authors.initials: BA
authors.lastname: Pereira
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, Brazil.
authors.forename: Luzia Monteiro de Castro
authors.initials: LM
authors.lastname: Côrtes
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, Brazil.
authors.forename: Luiz Filipe Gonçalves
authors.initials: LF
authors.lastname: de Oliveira
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapia, Ensino e Bioprodutos, Rio de Janeiro, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Henriques-Pons
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Imunoparasitologia, Rio de Janeiro, Brazil.
authors.forename: Lea Cysne
authors.initials: LC
authors.lastname: Finkelstein
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, Brazil.
authors.forename: Vitor Francisco
authors.initials: VF
authors.lastname: Ferreira
authors.affiliation: Universidade Federal do Rio de Janeiro, Núcleo de Pesquisas de Produtos Naturais, Rio de Janeiro, Brazil.
authors.forename: Paula Fernandes
authors.initials: PF
authors.lastname: Carneiro
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Imunologia Clínica, Rio de Janeiro, Brazil.
authors.forename: Rosa Teixeira
authors.initials: RT
authors.lastname: de Pinho
authors.affiliation: Fundação Oswaldo Cruz, Programa de Computação Científica, Rio de Janeiro, Brazil.
authors.forename: Ernesto Raul
authors.initials: ER
authors.lastname: Caffarena
authors.affiliation: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, Brazil calves@ioc.fiocruz.br.
authors.forename: Carlos Roberto
authors.initials: CR
authors.lastname: Alves
mesh_terms: D000818:Animals; D000976:Antipain / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D003198:Computer Simulation; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology*; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D015842:Serine Proteinase Inhibitors; D000976:Antipain; D012697:Serine Endopeptidases; C090703:oligopeptidase B; C415043:alpha-lapachone