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Targeting the Leishmania kinome for the development of novel anti-parasitic strategies

Targeting the Leishmania kinome for the development of novel anti-parasitic strategies

Objective

Visceral leishmaniasis is caused by the protozoan parasites Leishmania donovani and Leishmania infantum and is a potentially fatal disease in endemic areas around the world. During the infectious cycle, Leishmania alternate between the insect promastigote stage and the vertebrate aflagellate amastigote stage that proliferates inside infected host macrophages provoking the pathology of the disease. This consortium uses a highly interdisciplinary approach to reveal Leishmania signaling molecules associated with amastigote virulence, with the major aim to exploit parasite-specific pathways for anti-leishmanial drug development. We use innovative drug screening concepts not applied previously on parasitic systems. We will utilize visual high-content screening to discover compounds capable to kill intracellular Leishmania amastigotes without deteriorating the host cell. This phenotype-based strategy relies on fluorescent parasites and macrophages as read-outs and will allow simultaneous assessment of anti-leishmanial activity and host cell toxicity under physiological conditions. We will apply a target-based strategy utilizing recombinant Leishmania protein kinases for inhibitor identification and structure-guided drug design. The identification of appropriate target kinases, with only limited homology to their mammalian counterparts will rely on in silico analysis by applying novel bioinformatic tools developed by consortium members, and in vitro assay based on their phospho-transferase activity towards recombinant Leishmania phospho-proteins. The major objectives of this proposal are (i) to screen small molecule and peptide libraries for hit compounds with leishmanicidal activity using phenotype- and target-based strategies, (ii) to identify anti-parasitic lead compounds and assess their pharmacokinetic profiles using cell-culture and experimental infection models for leishmaniasis, and (iii) to initiate lead optimization by structure-based drug design.

Coordinator

INSTITUT PASTEUR

Address

Rue Du Docteur Roux 25-28
75724 Paris Cedex 15

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 823 120

Administrative Contact

Nadia Khelef (Dr.)

Participants (12)

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INSTITUT PASTEUR KOREA

South Korea

INSTITUT PASTEUR DE TUNIS

Tunisia

EU Contribution

€ 90 180

INSTITUT PASTEUR DE MONTEVIDEO

Uruguay

EU Contribution

€ 81 888

TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY

Israel

EU Contribution

€ 255 720

LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER

United Kingdom

EU Contribution

€ 205 262

UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA

Italy

EU Contribution

€ 182 077

AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS

Spain

EU Contribution

€ 241 287

FUNDACIO CENTRE DE REGULACIO GENOMICA

Spain

EU Contribution

€ 229 162

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS

France

EU Contribution

€ 236 157

IP RESEARCH CONSULTING SASU

France

EU Contribution

€ 234 120

Universitat Pompeu Fabra

Spain

EU Contribution

€ 233 259

TECHNISCHE UNIVERSITAET BRAUNSCHWEIG

Germany

EU Contribution

€ 40 000

Project information

Grant agreement ID: 223414

Status

Closed project

  • Start date

    1 October 2008

  • End date

    31 March 2012

Funded under:

FP7-HEALTH

  • Overall budget:

    € 4 491 633

  • EU contribution

    € 2 852 232

Coordinated by:

INSTITUT PASTEUR

France

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