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© IP Research Consulting 2014
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Objectives

Challenging the global burden of trypanosomatid disease

An increasing number of European and global efforts have been set up in the public sector  over recent years in an attempt to correct the bleak outlook in anti-kinetoplastid  chemotherapy.  Such initiatives have focused on the identification and validation of parasite  drug targets and/or the setting up and running of high throughput physiological or target  based screening platforms. A portfolio of promising lead compounds has been identified from  physiological screens incorporating both novel drug candidates and FDA approved drugs.  Here, we bring such promising initiatives together with key experts in industry and academia  to create a unique and powerful drug discovery platform with the common objective of  advancing promising laboratory-driven discoveries into clinical utility.    The KINDReD consortium’s infrastructure for parasite  screening integrates five leading academic laboratories  in Europe (Portugal, United Kingdom and Switzerland),  the United States of America (California) and South  America (Brazil) with high throughput screening (HTS)  facilities equally distributed between all three major  kinetoplastid parasites. Follow-up medicinal chemistry  and ADMET expertise will be spear-headed by the  industrial partners and several academic members of  the consortium. Intracellular amastigote screening will  be employed as the most relevant for Leishmania spp  and Trypanosoma cruzi. Compound libraries (focused,  diversity oriented or natural) will be screened on this  platform, as well as compound series devised through  target screening and in silico approaches - led by  research intensive European SMEs.  High-value  validated protein targets will be carefully chosen and all  available kinetoplastid parasite homologues will be screened and compared to their human  homologue(s) to establish selectivity.   This is particularly important when determining  differential ligand-binding efficiency, a key element to identify optimal starting points in  fragment based drug design. Promising lead compounds, such as bisnapthalimidopropyl  polyamine inhibitors of tubulin deacetylase, will undergo optimisation for efficacy and  toxicology in cell-based and then animal disease models.    Toxicological markers will be evaluated in human cell lines prior to toxicity (acute, subacute  and chronic) testing in lower and then higher mammals.  In parallel, and in line with the US  Food and Drug Administration’s (FDA’s) Critical Path Initiative, several check-point controls  will be built into the pipeline to flag, identify and allow early correction of potential safety or  efficacy issues. These will include (i) a systems biology approach to identify and validate both  drug on-target and off-target interactions (potential toxicity markers) via activity-based  chemoproteomics (ii) ‘uptake and metabolism’ as potential modulators of drug efficacy and/or  resistance and (iii) the establishment of a firm set of criteria for drug efficacy and safety in  kinetoplastid chemotherapies. Our goal is to strengthen, inform and advance the current drug  development pipeline in order to achieve at least one new Phase I clinical candidate for one  or more trypanosomatid diseases commensurate with the lifetime of the proposed project. 

Scientific programme

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© IP Research Consulting 2014
Objectives