Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors

Autor(es):Mostrar menos -

Tunes, Luiza G. ^[1] ; Morato, Roberta E. ^[1] ; Garcia, Adriana ^[2] ; Schmitz, Vinicius ^[2] ; Steindel, Mario ^[3] ; Correa-Junior, Jose D. ^[4] ; Dos Santos, Helio F. ^[2] ; Frezard, Frederic ^[5] ; de Almeida, V, Mauro ; Silva, Heveline ^[6] ; Moretti, Nilmar S. ^[7] ; de Barros, Andre L. B. ^[8] ; do Monte-Neto, Rubens L. ^[1]

Afiliação do(s) autor(es)

^[1] Fundacao Oswaldo Cruz, Fiocruz Minas, Inst Rene Rachou, BR-30190009 Belo Horizonte, MG - Brazil

^[2] V, Univ Fed Juiz de Fora, Inst Ciencias Exatas, Dept Quim, BR-36036900 Juiz De Fora - Brazil

^[3] Univ Fed Santa Catarina, Dept Microbiol Imunol & Parasitol, BR-88040900 Florianopolis, SC - Brazil

^[4] Univ Fed Minas Gerais, Dept Morfol, BR-31270901 Belo Horizonte, MG - Brazil

^[5] Univ Fed Minas Gerais, Dept Fisiol & Biofis, BR-31270901 Belo Horizonte, MG - Brazil

^[6] Univ Fed Minas Gerais, Dept Quim, BR-31270901 Belo Horizonte, MG - Brazil

^[7] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, BR-04023062 Sao Paulo - Brazil

^[8] Univ Fed Minas Gerais, Fac Farm, BR-31270901 Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS INFECTIOUS DISEASES; v. 6, n. 5, p. 1121-1139, MAY 8 2020.
• Citações Web of Science: 0

Resumo

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. infant= and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 mu M. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 mu M. 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. (AU)

• Processo FAPESP: 18/09948-0 - Estudo da acetilação proteica em Leishmania
• Beneficiário: Nilmar Silvio Moretti
• Modalidade de apoio: Auxílio à Pesquisa - Regular