Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes.
Godwin U EbilomaEvangelos KatsoulisJohn O IgoliAlexander I GrayHarry P de KoningPublished in: Scientific reports (2018)
Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC50 (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8 h of incubation with the compound, the equivalent of a single generation time. This was accompanied by DNA fragmentation as shown by Terminal deoxynucleotidyl transferase dUTP Nick-End Labelling (TUNEL) assays. HDK-20 also induced a fast and profound depolarisation of the parasites' mitochondrial membrane potential and depleted intracellular ATP levels of T. brucei. Overall, HDK20 showed a multi-target mechanism of action, which provides a biochemical explanation for the promising anti-trypanosomatid activity in our previous report.
Keyphrases
- cell cycle
- drug discovery
- single molecule
- circulating tumor
- cell proliferation
- cell free
- drug induced
- oxidative stress
- high throughput
- single cell
- cancer therapy
- nucleic acid
- intellectual disability
- early onset
- trypanosoma cruzi
- plasmodium falciparum
- energy transfer
- reactive oxygen species
- gram negative
- circulating tumor cells
- autism spectrum disorder
- human health
- cell therapy
- stress induced