Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent Trypanothione reductase inhibitors
Arquivos
Data
2020
Autores
Tunes, Luiza G.
Morato, Roberta E.
Garcia, Adriana
Schmitz, Vinicius
Steindel, Mario
Correa-Junior, Jose A.D.
Santos, Helio F. Dos
Frezard, Frederic
Almeida, Mauro V. de
Silva, Heveline
Orientadores
Tipo
Artigo
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Resumo
The drugs currently used to treat leishmaniases have limitations
concerning cost, e!cacy, 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 !M. All gold(I) complexes were potent inhibitors of
trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8
!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 pro"les 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.