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Preclinical pipeline- research overview

Integration of physiological and target based assays with chemoproteomic

drug profiling and early ADMETox and metabolism studies.

The consortium will unify and advance the prior art, gaining access to corporate compound  libraries and natural compounds, which have yet to be screened against these parasites, as  well as de novo fragment-based drug design (GFTY, NOVA, USTA, PHX). Several of the  partners have already completed HTS campaigns with large diversity oriented or focused  compound libraries, as well as the screening of a comprehensive set of FDA approved drugs  against all three major kinetoplastid parasites (www.cdipd.org). The best of these drug leads  have demonstrated efficacy in animal models, some with promising safety and ADME  characteristics. A picture is emerging of the potential druggability of the parasite’s cellular  machinery although in many cases the trypanocidal mode of drug action, or lack of it for some  potent target-selected compounds, remains unknown.    Possibly, one of the most intriguing recent observations was the relatively large number of  FDA approved compounds that inhibit T. cruzi intracellular proliferation by ≥ 53 % (n=55, ~ 6%  of the compounds tested) and L. donovani by ≥ 60%  (n=27, ~ 3%) at 10 μM outlining the strong possibility of  drug repurposing for parasite treatment regimens.  Nonetheless, the therapeutically active concentration  remains relatively high (low μM range) with poor  selectivity for most of these drugs.  Both of these factors  compare unfavourably with the selective inhibition in the  low nM range that is typical of target-designed drugs.  Hence, improvements might be made in physiological  assays by characterising the mode of action, allowing  identification of the cellular target(s) and improving  potency by structure–based design. Conversely, many  potent lead compounds identified using isolated protein  targets have failed to demonstrate any significant  trypanocidal effect in cell proliferation assays. Bluntly,  neither assay format alone tells us much about drug  action from a cellular perspective. It is increasingly clear that progress in trypanosomatid drug  discovery will require foreground knowledge concerning the uptake, metabolism and cellular  targets of putative lead compounds before firm advances can be made in target-based drug  design. To achieve this, a platform integrating both physiological cell-based screening and  target-based design will be established and cross-referenced through activity-based drug  target profiling on whole cells (chemoproteomics and drug metabolomics). We will establish  factors governing the bioavailability of drugs in parasite culture and ascertain how they  interact with their intended and non-desired targets. Such data will be crucial to pinpoint  potential toxicology issues early in the process, guide lead optimisation for enhanced efficacy  and safety, thus reducing the attrition rate of compounds in development. These data will be  made available as an open resource for use by the scientific community. 

Scientific programme

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© IP Research Consulting 2014
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