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Engineering substrate-based inhibitors of Plasmodium SUB1, a potential target for Malaria treatment.

Projektbeschreibung

Neuartige Zielstruktur für Malariatherapien

Malaria ist noch immer eine der häufigsten durch Parasiten verursachte Krankheiten. Da diese Parasiten aber neue und sich ausbreitende Resistenzen gegen herkömmliche Wirkstoffe entwickeln, muss kontinuierlich an neuen Malariamedikamenten und neuen therapeutischen Zielstrukturen geforscht werden. Schwerpunkt des EU-finanzierten Projekts SUBUN ist die Forschung an Inhibitoren des Plasmodium-spezifischen Subtilisins SUB1, einer Protease, die am Wirtszellaustritt des Parasiten aus infizierten menschlichen Zellen beteiligt ist. Mittels kombinierter Expertise aus den Bereichen medizinische Chemie, Biochemie, Strukturbiologie und Parasitologie sollen wirksame und selektive SUB1-Inhibitoren für den prophylaktischen wie auch therapeutischen Einsatz identifiziert werden. Vor allem sollen diese Inhibitoren auf alle Stadien des Parasitenlebenszyklus abzielen und damit die WHO-Kriterien für Malariamedikamente erfüllen.

Ziel

The Researcher AK Puszko will be in charge of the development of peptidase inhibitors with potential interest in the treatment of Malaria.
Malaria is the most important human parasitic disease and multi-resistant parasites seriously threaten its treatment and control. The situation strengthens the constant need to fuel the antimalarials pipeline with candidates active on new targets, expressed at essential stages of Plasmodium. The egress of merozoites from infected host cells is such a pivotal step that strictly depends upon parasite proteases, including a novel highly promising target, the Plasmodium-specific subtilisin SUB1, for which no useful inhibitor has been discovered yet. SUB1 plays a key role in the egress from hepatocytes and erythrocytes, including for male gametes (involved in parasite’s transmission via the Anopheles vector), indicating that an inhibitor would have both prophylactic and therapeutic value and obey to most severe WHO’s criteria of future anti-malarials, i.e. targeting all stages of parasite life cycle. Based on Hosts’ promising results, including the resolution of crystallographic structures of SUB1-inhibitor complexes, the SUBUN project aims at identifying highly potent and selective SUB1 inhibitors, active against parasite growth in vitro and in vivo. Such innovative pre-lead candidate(s) will be patented before results dissemination within academia, industry and to wider audience.
This project will combine expertise in molecular design, medicinal chemistry, biochemistry, structural biology and parasitology. In this multidisciplinary context, the project will benefit AK Puszko who will gain extensive knowledge in new fields well established in the Host and secondment Host laboratories. This, together with scientific and transferable trainings, opportunities to develop network, communication to non-scientific audience, will strengthen her ability to become a leader in the new topic and establish her own research group in the future.

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Koordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Netto-EU-Beitrag
€ 196 707,84
Adresse
Rue michel ange 3
75794 Paris
Frankreich

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Region
Ile-de-France Ile-de-France Paris
Aktivitätstyp
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