LEISHDRUG

EC contribution

: € 2.852.232

Duration

: 36 months

Starting date

: 01/10/2008

Funding scheme

: Focused research project

Contract/Grant agreement number

: 223414

Project web-site

: www.leishdrug.org

Keywords: Leishmaniasis, high content visual screening, phospho-proteomics, target-based screening, kinase

Problem:

Chemotherapy remains the most important element in the control of VL as there are currently no vaccines to prevent VL infection. All current treatments suffer from significant drawbacks, i.e. parenteral route of administration, length of treatment (21 to 28 days), toxicity, or/and cost which limits their utilization in disease endemic areas. In addition, the drugs currently in clinical development are either reformulations of earlier medicines, combination therapies or the result of therapeutic switching and therefore do not offer new alternatives to patients suffering from leishmaniasis. Despite some progress for VL in treatment options in India (but not East Africa), no ideal drugs are available that fulfill the major requirements for efficient anti-leishmanial therapy, including high efficacy, low toxicity, easy administration, low costs, and avoiding occurrence of drug resistant parasites. Novel concepts towards identification and optimization of drug leads are urgently needed to overcome the current situation and more efficiently combat and eventually eradicate this deadly disease.

Aim:

The FP7-LEISHDRUG consortium provides a unique platform that aims to

1. develop therapeutic tools for neglected infectious diseases caused by Trypanosomatidae,
2. set up and deploy an integrated multidisciplinary approach for the development of new drugs based on recent scientific advances in areas such as genomics and proteomics,
3. strengthen capacity building of two ICPC countries (Tunisia and Uruguay) for understanding and control of these diseases through networking and training scientists from endemic areas at the post-doctoral and pre-doctoral levels,
4. provide mutual benefits to develop and exploit targets and lead compounds applicable and affordable for use in disease endemic countries, the latter objective benefiting from the participation of one SME with commercial interest in anti-parasitic drug development.

Expected results:

The LEISHDRUG consortium will have a significant impact on the following three main areas:

1. Establishing an international network of European and ICPC researchers to develop new strategies to combat leishmaniasis

The creation of the LEISHDRUG consortium will have an immediate impact on reinforcing European research on trypanosomatid control and on fostering European interactions with programs and partners in developing countries. Our proposal connects leading scientists from 5 European countries (France, Spain, UK, Italy, Germany), Israel, South Korea, and two ICPC countries, Uruguay and Tunisia. LEISHDRUG thus will provide an important platform to coordinate the currently rather fragmented and insulated research efforts in the area of anti-leishmanial drug development. In agreement with the Barcelona objectives of education, training and innovation, the consortium will promote exchange of personnel, material, and knowledge. This project will include training and scientific exchange activities to enhance the research capacity and transfer technologies among the partners, especially among young investigators from developing countries. These plans imply the mobility of graduate students, post-doctoral fellowships and staff members. By transferring scientific information and excellence to ICPC partners, the present project will provide important contributions to building capacities for basic research in bioinformatics, proteomics, imaging, and structure-based drug design. In particular, the project will strengthen capacities in bioinformatics at the Pasteur Institute in Tunis and will allow this partner to move into the field of in silico analysis of pathogens and disease vectors, and drug design. Moreover, the principal investigator at IPT, Dr. Alia Benkahla, brings in an important expertise in capacity building as she (i) has co-organized a series of scientific events on the African continent, (ii) is member of the executive committee of the African Society of Bioinformatics and Computational Biology (ASCBC), and (iii) has contacts with several WHO officers and members of the trypanosomatidae community. The consortium will take advantage of this situation and recruit talented PhD students and Post-Docs from ICPC for the project.


2. Discovery of new classes of lead compounds for curing leishmaniasis

The major long-term impact of LEISHDRUG lies in the identification of lead compounds against Leishmania and related trypanosomatids. Translating results to clinical applications is our ultimate goal. Small molecule-based therapies are, and probably will remain, the most important interventions for leishmaniasis. Within this project we propose to identify drug targets that impact on parasite-specific signaling pathways and in particular on the key influence of protein kinases. The identification of new lead compounds for such targets could translate into powerful therapeutic agents with potential broad applicability to other trypanosomatid pathogens. Efficient treatment will dramatically improve public health in disease-endemic countries. Infections due to Trpanosomatidae account for 122 000 deaths per year and over 4 million Disability Adjusted Life Years (DALY) (http://www.who.int/tdr/diseases). Reducing the burden of disease will have important consequences for the reduction of poverty and the economic development of ICPCs. This may be further enhanced by manufacture and commercialization through ICPC partners of inhibitors identified by the consortium.


3. Development of new technologies for studying Leishmania and other trypanosomatid parasites

We propose a highly innovative and multidisciplinary strategy for anti-leishmanial drug development that exploit advances in trypanosomatid genomics and uses bio-imaging, in silico biology, proteomics, peptide chemistry, and structure-based drug design. Conceivably, the application of these cutting edge technologies will significantly advance our understanding on the biology of trypanosmatid parasites, which is key element towards the development of new therapeutic approaches. The LEISHDRUG consortium will further contribute to the development of novel techniques with relevance to anti-microbial drug development, including imaging-based drug screening using intracellular parasites as readout for anti-microbial activity, and phosphoproteomic screens to identify novel drug targets and define inhibitory peptides. Recombinant parasites with modified protein kinase expression profiles or parasite-specific protein kinase inhibitors will be useful tools to study the role of protein phosphorylation (i) in regulation of parasite differentiation and virulence, (ii) in host immune subversion and physiopathology, and (iii) in the development of multi-drug resistance. Given the relative homology of Leishmania with other trypanosomatids, the results obtained by the consortium (protein kinase inhibitors, algorithms for screening, structural models, peptide libraries) will presumable be more broadly applicable to other trypanosomatids.

Potential applications:

Identification of novel lead compounds for anti-leishmanial therapy

Coordinator:

Partners: