Schlüsselwörter
(Englisch)
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Polyphosphate; Vtc4; parasite virulence; leishmaniasis; drug target; acidocalcisomes; protozoan parasites
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Forschungsprogramme
(Englisch)
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COST-Action CM0801 - New drugs for neglected diseases
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Kurzbeschreibung
(Englisch)
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The aim of this proposal is to validate polyphosphate synthase (Vtc4) as a drug target. Phosphate is accumulated as polyphosphate chains in yeast vacuoles or in acidocalcisomes of other lower eukaryotes. We recently reported the 3-D structure of yeast Vtc4 and its catalytic activity. The Leishmania major homologue of Vtc4 has been identified and can be studied as a potential drug target to fight leishmaniasis in a first step and for other trypanosomatids on a longer term.
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Partner und Internationale Organisationen
(Englisch)
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BE, BG, CH, DE, ES, FI, FR, GR, IL, IT, LT, NL, NO, PL, PT, SE, SI, UK
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Abstract
(Englisch)
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Treatment of trypanosomatid infections such as African sleeping sickness, Chagas disease and leishmaniasis are in need of new strategies and new compounds to fight these protozoan parasite infections. Present problems are a limited repertoire of available drugs, which often show low potency and/or high toxicity, together with an arising resistance to current treatments. The main aim of our proposal was to test the validity of the polyphosphate synthase (Vtc4) as a drug target. Inorganic polyphosphate (polyP), a multifunctional and ubiquitous polymer, was found to be involved in several cellular processes, such as osmoregulation, adaptation to stress and virulence of pathogens. Therefore, we decided to investigate the importance of polyP and Vtc4 in the protozoan parasite Leishmania in a first term and for other trypanosomatids on a longer term. The fact that information about Vtc4 structure, Vtc complex configuration, enzymatic activity and methodology is available in yeast is extremely useful. Our results suggest that Leishmania major Vtc4 (LmjVtc4) is indeed involved in polyP synthesis and that no other enzyme can complement for this function. Further, our data suggested that polyP levels fluctuated during the parasite life cycle, and that absence of Vtc4 protein and polyP impaired parasite virulence in macrophages (in vitro) and in mice (in vivo). Interestingly, polyP seems to be implicated in resistance to the temperature shift encountered by the parasite when entering the mammalian host. These results indicated that Vtc4 might be important for the survival and proliferation of the parasite inside the host and therefore could be used as a therapeutic target, most likely in combination with other molecules.
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Datenbankreferenzen
(Englisch)
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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: C09.0045
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