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Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2 '-de-N-Methylaplysinopsin

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Autor(es):
Romanelli, Maiara M. ; Amaral, Maiara ; Thevenard, Fernanda ; Cruz, Lucas M. Santa ; Regasini, Luis O. ; Migotto, Alvaro E. ; Lago, Joao Henrique G. ; Tempone, Andre G.
Número total de Autores: 8
Tipo de documento: Artigo Científico
Fonte: ACS OMEGA; v. 7, n. 32, p. 10-pg., 2022-08-04.
Resumo

Chagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2 '-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 mu M, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic- pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations. (AU)

Processo FAPESP: 17/50333-7 - Plano de desenvolvimento institucional em pesquisa do Instituto Adolfo Lutz (PDIp)
Beneficiário:Carlos Henrique Camargo
Modalidade de apoio: Auxílio à Pesquisa - Programa Modernização de Institutos Estaduais de Pesquisa
Processo FAPESP: 21/04464-8 - Protótipos microbianos e vegetais como candidatos a fármacos para protozooses negligenciadas e bactérias multirresistentes
Beneficiário:André Gustavo Tempone Cardoso
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica
Beneficiário:João Henrique Ghilardi Lago
Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular