Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent Trypanothione reductase inhibitors

dc.citation.epage1121-1139
dc.citation.issue5
dc.citation.volume6
dc.contributor.authorTunes, Luiza G.
dc.contributor.authorMorato, Roberta E.
dc.contributor.authorGarcia, Adriana
dc.contributor.authorSchmitz, Vinicius
dc.contributor.authorSteindel, Mario
dc.contributor.authorCorrea-Junior, Jose A.D.
dc.contributor.authorSantos, Helio F. Dos
dc.contributor.authorFrezard, Frederic
dc.contributor.authorAlmeida, Mauro V. de
dc.contributor.authorSilva, Heveline
dc.contributor.authorMoretti, Nilmar S. [UNIFESP]
dc.contributor.authorde Barros, Andre L. B.
dc.contributor.authorMonte-Neto, Rubens L. do
dc.contributor.authorLatteshttp://lattes.cnpq.br/2131472726202687pt_BR
dc.date.accessioned2021-11-29T12:53:56Z
dc.date.available2021-11-29T12:53:56Z
dc.date.issued2020
dc.description.abstractThe 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.pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipIDCNPq: 424729/2018pt_BR
dc.description.sponsorshipIDFAPESP: 2018/09948-0pt_BR
dc.identifier.doihttps://dx.doi.org/10.1021/acsinfecdis.9b00505pt_BR
dc.identifier.urihttps://hdl.handle.net/11600/62321
dc.languageengpt_BR
dc.publisherACS Publicationspt_BR
dc.relation.ispartofACS Infectious Diseasespt_BR
dc.rightsAcesso abertopt_BR
dc.subjectGold(I) complexespt_BR
dc.subjectLeishmaniasispt_BR
dc.subjectAntileishmanialpt_BR
dc.subjectMetallodrugspt_BR
dc.titlePreclinical gold complexes as oral drug candidates to treat leishmaniasis are potent Trypanothione reductase inhibitorspt_BR
dc.typeArtigopt_BR
unifesp.campusEscola Paulista de Medicina (EPM)pt_BR
unifesp.departamentoMicrobiologia, Imunologia e Parasitologiapt_BR
unifesp.graduateProgramMicrobiologia e Imunologiapt_BR
unifesp.knowledgeAreaOutrapt_BR
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