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

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...

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Veröffentlicht in:ACS infectious diseases 2020-05, Vol.6 (5), p.1121-1139
Hauptverfasser: Tunes, Luiza G, Morato, Roberta E, Garcia, Adriana, Schmitz, Vinicius, Steindel, Mario, Corrêa-Junior, José D, Dos Santos, Hélio F, Frézard, Frédéric, de Almeida, Mauro V, Silva, Heveline, Moretti, Nilmar S, de Barros, André L. B, do Monte-Neto, Rubens L
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container_end_page 1139
container_issue 5
container_start_page 1121
container_title ACS infectious diseases
container_volume 6
creator Tunes, Luiza G
Morato, Roberta E
Garcia, Adriana
Schmitz, Vinicius
Steindel, Mario
Corrêa-Junior, José D
Dos Santos, Hélio F
Frézard, Frédéric
de Almeida, Mauro V
Silva, Heveline
Moretti, Nilmar S
de Barros, André L. B
do Monte-Neto, Rubens L
description 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.
doi_str_mv 10.1021/acsinfecdis.9b00505
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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. 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title Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors
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