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New insights into the molecular mechanisms of anthelmintic proanthocyanidins

Subject Area Parasitology and Biology of Tropical Infectious Disease Pathogens
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 423277515
 
Final Report Year 2024

Final Report Abstract

Eight of the 18 Neglected Tropical Diseases covered by WHO are caused by helminths. During the search for plant derived natural products with anthelmintic activity an ethnopharmacological approach in West Africa pinpointed several plants used traditionally against nematodes. Detailed phytochemical and functional investigations revealed oligomeric proanthocyanidins PAC as active components. Using defined B-type PACs from Combretum mucronatum it was shown that these compounds interact with C. elegans surface proteins, changing biomechanical properties of the cuticle, leading to impairment of molting, exshetment and locomotion. On molecular level the expression of prolin-rich defense proteins of C. elegans (T22D1.2, clx-1) has been shown. Anthelminitic activity of PAC has been shown in different animal intestinal nematodes. Influence of PAC on gene expression of selected soil-transmitted helminths was investigated. The PAC enriched extract was investigated in vivo in goats, indicating concentration-dependent anthelmintic effects and significant lower worm burden compared to the untreated control. For investigation if the observed anthelmintic effects of PAC (condensed tannins) is due to a specific chemical structure or to a protein-binding, tannin-like effect, comparative studies were performed with a different chemical class of tannins, hydrolysable ellagitannins (HG), obtained from Phyllantus urinaria, widely used in Africa for treatment of helminths. It got obvious that anthelmintic activity is due to the adstringent character of the polyphenols and is not specifically related to defined structural features of the molecules, which do not contribute to protein-denaturing properties. PAC and HG were investigated also against human intestinal nematodes (Trichuris trichuriua) from natural infected human population. PAC and HG exert concentration-dependent anthelmintic effects. The activity, however, significantly decreased upon faecal metabolism, indicating that the anthelmintic activity is mainly due to PAC and HT and not caused by the respective faecal metabolites. Further on, we investigated the use of anthelmintic plants in West-Africa, and summarize the most relevant herbal materials. Despite the wide use, the pharmaceutical quality situation (identity, purity, content) in Africa is difficult. Therefore, current literature on methodological approaches used for quality control of herbal medicines was critically assessed to evaluate gaps associated with existing strategies, and to make recommendations for future improvements. Using these aspects, detailed analytical investigations were performed for C. mucronatum. Especially the development of ICH-validated chromatographic protocols for identity, purity, content assay, and analytical specifications for consideration into pharmacopoeial monographs was a central aim of the project. Such monographs including ICH-validated analytical protocols have been published for C. mucronatum and P. urinaria.

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