New insights into the molecular mechanisms of anthelmintic proanthocyanidins

• Applicants: Professor Dr. Andreas Hensel; Professorin Dr. Eva Liebau; Professorin Christina Strube, Ph.D.
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423277515

Around 1.5 billion people worldwide suffer from an infestation with soil-transmitted helminthiasis with roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Ancylostoma duodenale, Necator americanus) being the most common parasites. The treatment of these diseases is based on only few drugs with essentially no available alternatives.During the search for plant derived natural products with anthelmintic activity, oligomeric proanthocyanidins (e.g. the trimeric flavan-3-ol “PC-1”) have been pinpointed as active compounds against the model organism C. elegans, and the intestinal parasites Toxocara cati and Trichuris vulpis. Transcriptome analysis indicated that PC1 strongly influenced the expression of specific genes in C. elegans (e.g. T22D1.2); potentially, the respective proteins could serve as molecular targets for the development of novel anthelmintics.The project does not aim to develop a new PC-based drug, but should help to identify new targets and to performed intensified investigations for characterizing the effects and specifity of PCs on these targets from different animal and human parasites. Research within the African-German network on anthelmintic polyphenols combines the activities of groups from Cameroon, Ghana and Germany. 3 work packages (WP) structure the questions to be answered: WP I will provide better understanding of the cellular and molecular targets of PC1. In a first step, nematode proteins that act as binding partners for PC1 will be identified, the functionality of T22D1.2 as a potential defense mechanism in C. elegans will be examined, followed by investigations how PC1 affects the intestinal system of C. elegans.WP II will investigate the anthelmintic activity of PC1 in animal parasites, using ex vivo and in vivo experiments. In a first step the influence of PC1 and related tannin-like compounds against intestinal parasites with zoonotic potential (Ancylostoma caninum, Ascaris suum, Toxocara sp., Trichuris suis) will be investigated, followed by animal studies of PC1-enriched extracts against Haemonchus contortus in goats.WP III includes activity tests of PC1 against human intestinal nematodes. Additionally, anthelmintic effects and respective molecular targets of this compound will be compared to those from structurally different hydrolysable tannins to clarify the question, how structural differences of polyphenols influence the same molecular targets. Moreover, phytochemical and analytical studies will be performed within WP III to improve quality aspects of herbal materials used for anthelmintic treatment in humans and livestock in Africa.The planned project is an interdisciplinary program of experts from different areas (molecular biology, veterinary medicine, parasitology, pharmaceutical science and analytical chemistry) and will provide an effective platform for research at the border between chemistry, medicine and infectiology, being in line with the “One Health Concept”.

• DFG Programme: Research Grants
• International Connection: Cameroon, Ghana
• International Co-Applicants: Professor Christian Agyare, Ph.D.; Dieudonne Ndjonka, Ph.D.; Emelia Oppong Bekoe, Ph.D.