The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi .

Autor:	Macedo CM; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Saraiva FMS; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Paula JIO; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Nascimento SB; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Hematologia, Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro, Brazil., Costa DSDS; Departamento de Química Orgânica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Costa PRR; Laboratório de Química Bioorgânica, NPPN, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Dias AG; Departamento de Química Orgânica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Paes MC; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.; Instituto Nacional de Ciência e Tecnologia - Entomologia Molecular (INCT-EM), Rio de Janeiro, Brazil., Nogueira NP; Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.; Instituto Nacional de Ciência e Tecnologia - Entomologia Molecular (INCT-EM), Rio de Janeiro, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in microbiology [Front Microbiol] 2021 Apr 15; Vol. 12, pp. 617504. Date of Electronic Publication: 2021 Apr 15 (Print Publication: 2021).
DOI:	10.3389/fmicb.2021.617504
Abstrakt:	Chagas disease, which is caused by Trypanosoma cruzi , establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi . LQB303 presented trypanocidal effect against intracellular [IC 50 /48 h = 2.6 μM] and extracellular amastigotes [IC 50 /24 h = 3.3 μM] in vitro , leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi , as well as reduction of "proton leak" (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and "ETS" (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration ("ROX") enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Macedo, Saraiva, Paula, Nascimento, Costa, Costa, Dias, Paes and Nogueira.)
Databáze:	MEDLINE
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