| Author | Tunes, Luiza Guimarães | |
| Author | Correa, Roberta Emilia Morato | |
| Author | Garcia, Adriana | |
| Author | Schmitz, Vinicius | |
| Author | Steindel, Mario | |
| Author | Corrêa-Junior, José D. | |
| Author | Santos, Hélio F. dos | |
| Author | Frézard, Frédéric | |
| Author | Almeida, Mauro V de | |
| Author | Silva, Heveline | |
| Author | Moretti, Nilmar S. | |
| Author | Barros, André L. B. de | |
| Author | Monte Neto, Rubens Lima do | |
| Access date | 2020-06-26T18:19:32Z | |
| Available date | 2020-06-26T18:19:32Z | |
| Document date | 2020 | |
| Citation | TUNES, Luiza Guimarães et al. Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors. ACS Infectious Diseases, v. 6, n. 5, p. 1121-1139, 2020. | pt_BR |
| ISSN | 2373-8227 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/41908 | |
| Language | eng | pt_BR |
| Publisher | ACS Publications | pt_BR |
| Rights | restricted access | pt_BR |
| Title | Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors | pt_BR |
| Type | Article | |
| DOI | 10.1021/acsinfecdis.9b00505 | |
| Abstract | The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Santa Catarina. Departamento de Microbiologia, Imunologia e Parasitologia. Florianópolis, SC, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Minas Gerais. Departamento de Morfologia. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Minas Gerais. Departamento de Química. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de São Paulo. Departamento de Microbiologia, Imunologia e Parasitologia. São Paulo, SP, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Minas Gerais. Faculdade de Farmácia. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil. | pt_BR |
| Subject | TR inhibition | pt_BR |
| Subject | Antileishmanial | pt_BR |
| Subject | Gold(I) complexes | pt_BR |
| Subject | Leishmaniasis | pt_BR |
| Subject | Metallodrugs | pt_BR |
| Subject | Oral treatment | pt_BR |
| Embargo date | 2100-01-01 | |
