Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes
Ebiloma, Godwin U. and Katsoulis, Evangelos and Igoli, John O. and Gray, Alexander I. and De Koning, Harry P. (2018) Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes. Scientific Reports, 8 (1). pp. 1-9. 4613. ISSN 2045-2322
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Abstract
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.
Creators(s): | Ebiloma, Godwin U., Katsoulis, Evangelos, Igoli, John O., Gray, Alexander I. and De Koning, Harry P.; | Item type: | Article |
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ID code: | 63839 |
Keywords: | parasite physiology, target identification, Therapeutics. Pharmacology, Pharmacology (medical) |
Subjects: | Medicine > Therapeutics. Pharmacology |
Department: | Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences |
Depositing user: | Pure Administrator |
Date deposited: | 24 Apr 2018 14:13 |
Last modified: | 28 Dec 2020 02:03 |
Related URLs: | |
URI: | https://strathprints.strath.ac.uk/id/eprint/63839 |
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