Key words
(English)
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Drug discovery; novel diamidines; livestock diseases; Trypanosoma evansi; Babesia spp.; in vitro screening; animal models; lead optimization
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Research programs
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COST-Action B22 - Drug development for parasitic diseases
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Short description
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Funds are requested to screen available novel diamidines for in vitro activity, cytotoxicity and efficacy in rodent models against T. evansi and Babesia spp. In the frame of two international projects (funded by the Gates Foundation and the 'Medicines for Malaria Venture') these compounds demonstrated its superior activity against the agents of human African trypanosomiasis and malaria. Preliminary experiments in our laboratory have shown activity of selected diamidines against the two animal pathogenic protozoans T. evansi (causing a disease called 'Surra' affecting horses, camels, cattle and water buffalo mainly) and Babesia spp. (causing disease in cattle mainly and occasionally also in humans). In vitro screening and mouse models will be used to determine the efficacy of the compounds. The data will be analysed based on structure-activity relationship which will allow us to select or have synthesized potentially more active molecules. Secondary in vitro and vivo experiments (e.g. time-dose studies, resistant strains, ease of development of drug resistance) will support the selection of lead compounds for studies in larger mammalian hosts together with available data on toxicity, pharmacokinetics and metabolism from the Gates and MMV projects. The link to these two projects and consortia will create synergies and will add much value to the proposed project.
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Partners and International Organizations
(English)
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AT, BE, BG, CZ, DK, FR, DE, EL, IE, IL, IT, LT, LU, NL, PT, SI, ES, SE, CH, UK
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Abstract
(English)
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Protozoan parasites affect domestic animals by causing loss of milk and meat production, abortion and death of infected individuals and thus, they have a great economic impact mainly in developing regions. This project focused on Trypanosoma evansi and Babesia spp., two animal pathogenic protozoans. T. evansi causes surra, a wasting disease associated with equines, camels, cattle and other domestic animals which are common in Africa, Asia and South America. Transmission occurs mechanically by biting flies. Babesiosis is a tick-borne infection caused by intraerythrocytic parasites that affect wild and domestic animals worldwide. While bovine disease is of prime importance, babesiosis is also gaining interest as an emerging zoonosis in humans. Treatment of both surra and babesiosis is dependent on a very limited number of drugs and the problem of emerging drug resistance calls for new effective and readily available drugs. It has been known since the 1940s that dicationic molecules exhibit antiprotozoal properties. We have tested over 200 diamidines, aromatic dicationic molecules, in vitro against T. evansi and B. divergens strains. Compounds with an IC50 value below 20 ng/ml and no acute toxicity proceeded to a T. evansi and B. microti mouse model, where parasitemia was monitored to determine survival and/or recrudescence. The test compounds demonstrated excellent activities in both animal models and some of them were even able to cure the mice at remarkably low doses. Furthermore, a majority of diamidines proved to be clearly more potent than the standard drugs, eg. diminazene aceturate. For T. evansi, the minimal curative dose in mice was determined and toxicity, effectiveness as well as pharmacokinetic properties of three new diamidines are currently being evaluated in a goat model. The pilot study will provide important information and will help to identify a new drug candidate for clinical trials.
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References in databases
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C04.0104
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