LEISHDRUG

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

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 Obiettivo del progetto (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.'

Introduzione (Teaser)

The parasitic diseases known as Leishmaniases have plagued man for centuries. Because of their severity - sometimes with fatal consequences - the EU has stepped up efforts to find a cure.

Descrizione progetto (Article)

Visceral Leishmaniasis is a severe infection caused by Leishmania parasites that infect skin and inner organs. Worryingly, parasites have developed resistance to some of the current treatments available and the World Health Organisation has been pressing researchers to find more effective drugs.

In response, the EU has jointly funded the http://www.leishdrug.org (LEISHDRUG) (Targeting the Leishmania kinome for the development of novel anti-parasitic strategies) project. Through a multidisciplinary approach, researchers identified molecules associated with the development of the disease-causing amastigote stage.

Using innovative drug-screening concepts, which have never been applied to parasitic systems, researchers homed in on compounds that can eradicate the parasites without harming the host cell. The strategy relies on fluorescent parasites and macrophages (a type of white blood cell) to measure the efficacy of the new compounds and assess host cell toxicity. Second, the scientists utilised recombinant Leishmania protein kinases for inhibitor identification and structure-guided drug design.

LEISHDRUG established a unique collection of compounds, covering more than 35 000 molecules with synthetic or medicinal chemistry traceability. These were applied in the kinase-based screening campaigns and are also available for other drug development projects undertaken by project partners.

The tools have been successfully applied to identify anti-leishmanial hit compounds. In particular, the phenotypic screen has isolated 15 effective compounds out of a total 2 000 compounds. In a complementary target-based assay, over 4 000 natural and synthetic compounds were screened identifying 11 hit compounds. Further work on the kinome revealed LmaMPK4 as a viable drug target that shows a series of highly parasite-specific regulatory residues with good druggability. Another group of promising targets includes parasite stress kinases.

A collaborative initiative, LEISHDRUG has achieved a world-class drug development platform supported by assay development, drug target identification with genetic validation. In vivo as well as in vitro assessment has produced anti-leishmanial drug candidates that can be further exploited for the development of novel therapies against this devastating diseases.