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https://www.arca.fiocruz.br/handle/icict/12538
A LUPANE-TRITERPENE ISOLATED FROM COMBRETUM LEPROSUM MART. FRUIT EXTRACTS THAT INTERFERES WITH THE INTRACELLULAR DEVELOPMENT OF LEISHMANIA (L.) AMAZONENSIS IN VITRO
Leishmania (L.) amazonensis
Combretum leprosum
Amastigotes
Macrophages
Antileishmanial activity
Author
Affilliation
Oswaldo Cruz Foundation. Malaria and Leishmaniasis Bioassays Platform. Porto Velho, RO, Brazil.
Oswaldo Cruz Foundation. Center of Studies for Biomolecules Applied to Health. Porto Velho, RO, Brazil.
Universidade Federal de Rondônia. Laboratory of Insect Bioecology. Porto Velho, RO, Brazil. / Oswaldo Cruz Foundation. Laboratory of Medical Entomology. Porto Velho, RO, Brazil.
Universidade Federal de Rondônia. Research Laboratory of Chemistry of Natural Products. Porto Velho, RO, Brazil.
Pontifícia Universidade Católica. Structural Biochemistry Laboratory. Porto Alegre, RS, Brazil.
Research Institute for Tropical Diseases in Rondônia. Laboratory of Molecular Epidemiology. Porto Velho, RO, Brazil.
Universidade Federal do Rio de Janeiro. Institute of Biophysics. Laboratory of Cellular Ultrastructure Hertha Meyer. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Center of Studies for Biomolecules Applied to Health. Porto Velho, RO, Brazil.
Universidade Estadual de Santa Cruz. Department of Biological Sciences. Ilheús, BA, Brazil.
Oswaldo Cruz Foundation. Center of Studies for Biomolecules Applied to Health. Porto Velho, RO, Brazil.
Universidade Federal de Rondônia. Laboratory of Insect Bioecology. Porto Velho, RO, Brazil. / Oswaldo Cruz Foundation. Laboratory of Medical Entomology. Porto Velho, RO, Brazil.
Universidade Federal de Rondônia. Research Laboratory of Chemistry of Natural Products. Porto Velho, RO, Brazil.
Pontifícia Universidade Católica. Structural Biochemistry Laboratory. Porto Alegre, RS, Brazil.
Research Institute for Tropical Diseases in Rondônia. Laboratory of Molecular Epidemiology. Porto Velho, RO, Brazil.
Universidade Federal do Rio de Janeiro. Institute of Biophysics. Laboratory of Cellular Ultrastructure Hertha Meyer. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Center of Studies for Biomolecules Applied to Health. Porto Velho, RO, Brazil.
Universidade Estadual de Santa Cruz. Department of Biological Sciences. Ilheús, BA, Brazil.
Abstract
Background: 3beta,6beta,16beta-trihydroxylup-20(29)-ene is a lupane triterpene isolated from Combretum leprosum fruit. The lupane group has been extensively used in studies on anticancer effects; however, its possible activity
against protozoa parasites is yet poorly known. The high toxicity of the compounds currently used in leishmaniasis
chemotherapy stimulates the investigation of new molecules and drug targets for antileishmanial therapy.
Methods: The activity of 3beta, 6beta, 16beta-trihydroxylup-20(29)-ene was evaluated against Leishmania (L.)
amazonensis by determining the cytotoxicity of the compound on murine peritoneal macrophages, as well as its
effects on parasite survival inside host cells. To evaluate the effect of this compound on intracellular amastigotes,
cultures of infected macrophages were treated for 24, 48 and 96 h and the percentage of infected macrophages
and the number of intracellular parasites was scored using light microscopy.
Results: Lupane showed significant activity against the intracellular amastigotes of L. (L.) amazonensis. The
treatment with 109 M for 96 h reduced in 80 % the survival index of parasites in BALB/c peritoneal macrophages.
At this concentration, the triterpene caused no cytotoxic effects against mouse peritoneal macrophages.
Ultrastructural analyses of L. (L.) amazonensis intracellular amastigotes showed that lupane induced some
morphological changes in parasites, such as cytosolic vacuolization, lipid body formation and mitochondrial swelling. Bioinformatic analyses through molecular docking suggest that this lupane has high-affinity binding with DNA topoisomerase.
Conclusion: Taken together, our results have showed that the lupane triterpene from C. leprosum interferes with L. (L.) amazonensis amastigote replication and survival inside vertebrate host cells and bioinformatics analyses strongly indicate that this molecule may be a potential inhibitor of topoisomerase IB. Moreover, this study opens major prospects for the development of novel chemotherapeutic agents with leishmanicidal activity.
Keywords
LupaneLeishmania (L.) amazonensis
Combretum leprosum
Amastigotes
Macrophages
Antileishmanial activity
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