Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2'-de- N -Methylaplysinopsin.
Maiara M RomanelliMaiara AmaralFernanda ThevenardLucas M Santa CruzLuis O RegasiniAlvaro E MigottoJoão Henrique Ghilardi LagoAndre Gustavo TemponePublished in: ACS omega (2022)
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 IC 50 values of 62 and 5.7 μM, 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.
Keyphrases
- trypanosoma cruzi
- high resolution mass spectrometry
- liquid chromatography
- oxidative stress
- optical coherence tomography
- mass spectrometry
- ms ms
- endothelial cells
- reactive oxygen species
- high glucose
- diabetic rats
- gas chromatography
- magnetic resonance imaging
- climate change
- risk assessment
- computed tomography
- combination therapy
- stress induced
- human health
- contrast enhanced