LEISHDRUG Consortium

Collaborative Project

 

 

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WP5 implicates Dr. Gerald Spaeth, head of the Parasite Virulence Unit at the Institut Pasteur (IP) in Paris, Prof. Dan Zilberstein, Head of the Molecular Parasitology laboratory at the Technion Israel Institute of Technology (IIT) in Haifa, and Iain Pemberton, CEO of the Photeomix (PHX) SME located in the east of Paris. WP4 will use forefront high throughput proteomics strategies established by partners 1, 5, and 11 to identify novel, stage-specific and essential phosphoproteins and phosphorylation sites [7, 42]. Based on protein homology, the Leishmania major kinome comprises 199 conserved homologs [14]. This sequence-based kinome however provides major limitations for drug target identification as it excludes potential parasite-specific atypical kinases without significant sequence conservation. We propose here a novel approach to identify such kinases in an unbiased way based on their phosphotransferase activity towards recombinant phosphoprotein and synthetic phosphopeptide substrates. Phosphopeptide sequences will be used by members of the consortium to a) develop peptide-based inhibitors (partners 8 and 12), b) identify protein kinases with good druggability that will provide leads for the target-based drug screening (partner 10) and c) structural-based drug design (partner 4). Furthermore, functional proteomics together with kinase activity assays will be used to validate putative kinases identified in silico (partners 3, 7, and 9), and to identify cellular targets of candidate compounds identified by the in situ screens (partners 1, 2, and 10).