Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes

Godwin U. Ebiloma, Evangelos Katsoulis, John O. Igoli, Alexander I. Gray, Harry P. De Koning

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

LanguageEnglish
Article number4613
Pages1-9
Number of pages9
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 15 Mar 2018

Fingerprint

Polyalthia
Clerodane Diterpenes
Trypanosoma brucei brucei
Trypanosomiasis
Diterpenes
DNA Nucleotidylexotransferase
Mitochondrial Membrane Potential
DNA Fragmentation
Drug Discovery
Biological Products
Cell Cycle
Parasites
Adenosine Triphosphate
Fluorescence
Drug Therapy
DNA

Keywords

  • parasite physiology
  • target identification

Cite this

Ebiloma, Godwin U. ; Katsoulis, Evangelos ; Igoli, John O. ; Gray, Alexander I. ; De Koning, Harry P. / Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 1-9.
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Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes. / Ebiloma, Godwin U.; Katsoulis, Evangelos; Igoli, John O.; Gray, Alexander I.; De Koning, Harry P.

In: Scientific Reports, Vol. 8, No. 1, 4613, 15.03.2018, p. 1-9.

Research output: Contribution to journalArticle

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