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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.

Field of science

  • /medical and health sciences/basic medicine/medicinal chemistry

Call for proposal

FP7-HEALTH-2007-B
See other projects for this call

Funding Scheme

CP-SICA - Collaborative project for specific cooperation actions dedicated to international cooperation partner countries (SICA)

Coordinator

INSTITUT PASTEUR
Address
Rue Du Docteur Roux 25-28
75724 Paris Cedex 15
France
Activity type
Research Organisations
EU contribution
€ 823 120
Administrative Contact
Nadia Khelef (Dr.)

Participants (12)

INSTITUT PASTEUR KOREA
South Korea
Address
Hawolgok Dong, Seongbuk Gu 39-1
136 791 Seoul
Activity type
Research Organisations
Administrative Contact
Kim Sung Eun (Ms.)
INSTITUT PASTEUR DE TUNIS
Tunisia
EU contribution
€ 90 180
Address
Place Pasteur 13
1002 Tunis
Activity type
Research Organisations
Administrative Contact
Fayçal Chaabane (Mr.)
INSTITUT PASTEUR DE MONTEVIDEO
Uruguay
EU contribution
€ 81 888
Address
Mataojo 2020
11400 Montevideo
Activity type
Research Organisations
Administrative Contact
Didier Pouzergues (Mr.)
TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Israel
EU contribution
€ 255 720
Address
Senate Building Technion City
32000 Haifa
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Silvia Birsan (Ms.)
LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
United Kingdom
EU contribution
€ 205 262
Address
Keppel Street
WC1E 7HT London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Penny Ireland (Ms.)
UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
Italy
EU contribution
€ 182 077
Address
Via Cracovia 50
00133 Roma
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Alessandro Finazzi Agro' (Prof.)
AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Spain
EU contribution
€ 241 287
Address
Calle Serrano 117
28006 Madrid
Activity type
Research Organisations
Administrative Contact
Carlos Manuel Abad Ruiz (Mr.)
FUNDACIO CENTRE DE REGULACIO GENOMICA
Spain
EU contribution
€ 229 162
Address
Carrer Doctor Aiguader 88
08003 Barcelona
Activity type
Research Organisations
Administrative Contact
Marta Balza (Ms.)
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France
EU contribution
€ 236 157
Address
Rue Michel Ange 3
75794 Paris
Activity type
Research Organisations
Administrative Contact
Florence Morineau (Ms.)
IP RESEARCH CONSULTING SASU
France
EU contribution
€ 234 120
Address
Quai Des Deux Ponts 31
93160 Noisy Le Grand
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Jane Sefton Uller (Dr.)
UNIVERSIDAD POMPEU FABRA
Spain
EU contribution
€ 233 259
Address
Placa De La Merce, 10-12
08002 Barcelona
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Eva Martin (Ms.)
TECHNISCHE UNIVERSITAET BRAUNSCHWEIG
Germany
EU contribution
€ 40 000
Address
Universitaetsplatz 2
38106 Braunschweig
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Conrad Kunick (Prof.)