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Workpackages

KINDReD was devised to meet the challenge of drug development for neglected kinetoplastid  diseases in the face of market failure to drive current innovations into clinical utility. The  consortium, bringing together innovators from academia and small industry alike, has devised  an efficient screening pipeline to accelerate the design, testing and approval of new  medicines against the etiological agents of Chagas disease, African sleeping sickness and  visceral leishmaniasis. Pre-clinical drug development remains a difficult process to control  with little certainty that lead candidates, however potent in vitro, will pass all of the rigorous  testing needed to ensure safety in clinical trials. For this reason, it is not appropriate to focus  only on a small subset of compounds with attractive anti-parasitic properties. Rather, the  pipeline is a continuous process that must be repopulated with new candidates to balance  those that fail the process. Past experience tells us a candidate is more likely to fail than  succeed; the process must be repeated until the true clinical candidate emerges.   The programme involves 12 WPs integrating 14 partners focusing on anti-parasitic drug  screening WPs (46 person years), ADMETox, PK and IM properties of the drug candidates  (34 person years). Accessory WPs account for 12 person years.

WP list

WP1 led by Prof. Jim McKerrow, Director of the Center for and Innovation in Parasitic  Diseases at the University of California San Francisco, provides the central focus for  screening new libraries of structurally-diverse small molecules, natural compounds and  target-based drug design sources. This resource spread over 5 centres worldwide (UCSF,  USTA, IBMC, PCU, FIOCRUZ) will undertake a large scale screening effort. Such effort will  be supported by experts in medicinal and structural chemistry who provide de novo synthesis  capabilities for natural and synthetic compounds as well as fragment based drug design. WP1  is the focal point for the discovery of new anti-kinetoplastid drugs, as only those drugs  showing efficacy against physiologically-relevant forms of the parasites will be selected for  further testing.   WP2, led by Dr Terry Smith (USTA) gathers together a wealth of genetically and/or chemically  validated enzymatic targets from several KINDReD partners for target-directed drug  discovery. Qualified drug screening assays have been developed for these targets suited to  the hit to lead discovery process as well as fragment-based drug design (FBDD).   WP3 is focused on industry-leading high content SPR (Dr T Neumann, GFTY) and structure-  based FBDD (Dr D Zeyer, NOVA)) using the tubulin deacetylase SIR2 as its primary target of  interest. WP4 led by Dr Helge Bode (GUF) follows on from the FP7 GAMEXP consortium providing the  focus on anti-parasitic properties of extracts from natural sources including under-represented  fungal sources and marine isolates.    WP5 led by the CEO of PHYL, Dr G Skorski, will develop innovative chemoproteomic  strategies to identify hit to target and ‘off’-target interactions as indicators of mode of action  and safety biomarkers.   WP6 investigates the mysteries of drug metabolism by the parasite as an innate mechanism  of drug resistance calling on extensive expertise in metabolite analysis from LEMM, led by Dr  A Pruvost, and targeting the underlying enzyme pathways themselves as potential points for  chemotherapeutic intervention.   WP7 turns its attention to the potential of drugs to induce unintentional immunomodulation  (IM) as a safety biomarker of drug-induced toxicity. These experiments, led by Dr O Assis  (FIOCRUZ), will be conducted on blood obtained from patients with Chagas (FIOCRUZ),  leishmaniasis (Dr S Singh, AIIMS) and healthy blood (PCU).   In WP8, compounds selected in WP1 are evaluated in a multiparametric in vitro screen of  organ-specific toxicity (led by Dr I. Ramos, INNO) with ADME properties carefully examined  for promising lead candidates. Effective ADME and toxicology are needed early in the drug  discovery process as these represent two areas in which most candidate drugs fail.  Nanoparticle encapsulation technology is proposed here for compounds showing poor  bioavailability.   WP9 encompasses the animal efficacy, safety and pharmacokinetic studies required to meet  the European Medicines Agency’s (EMA’s) criteria for PK/PD and safety data sufficient for the  filing of the application for first in-human trials. Led by Prof A. Cordeiro-da-Silva (IBMC),  testing will be performed in BALB/c mouse infection models. The most promising candidate(s)  will be tested in non human primates as the most appropriate non-human source necessary  for filing of the INM. PHX lead   WP10 (led by Dr Jane MacDougall, PHX) focusses on regulatory affairs and quality  assurance. It provides working focus on regulations and procedural aspects set out by the EU  directive of the European Parliament and the European Medicines Agency guidelines for the  registration for first-in-human clinical trials. It will also monitor aspects of Quality Management  and Standard Operating Procedures (SOPs) in support of safety risk assessment of  investigational new medicines and new chemical entities.  WP11 concerns management of financial (USTA) and other consortium coordination   activities. WP12 is involved in synergy activities with other FP7 funded anti-parasitic nelected disease  initiatives. 

Scientific programme

WP 1 to 5 WP 6 to 9 WP 10 to 12 next previous Workpackages