Ziel
The READ-UP project aims at identifying antimalarial drug candidates (1 candidate and two back-ups). The project starts from a hit identified in a first series to enlarge it and design other series through the different steps of drug discovery and hit to lead optimisation until the pilot scale production for further proceeding to pre-clinical studies. The natural antimalarial product artemisinin and its derivatives are increasingly important in the treatment of drug-resistant malaria as they are the most p otent antimalarials available, rapidly killing all blood stages of the malaria parasite. Artemisinins contain an endoperoxide bridge which plays a key role in the antimalarial activity with a mode of action starting from radical transient species initiated by the cleavage of this bridge. To improve the properties of artemisinins (solubility, pharmacokinetics and costs), many research groups have proposed synthetic analogues and the goal of a cheap, synthetic endoperoxide antimalarial has not been achieved y et. One of the major difficulties is located on the oxygen-oxygen bridge which is chemically unstable, leading to short in vivo half-life which remains a limiting factor. The READ-UP project starts from the unique mode of action of artemisinins to develop a totally new approach: initiate radical transient species within the parasitized red blood cell in such way that no endoperoxide bridge is required. A strong redox activity is generated during the intra-erythrocytic development of the parasite producing f ree radicals. Our innovative approach is to take advantage of this natural primary free radical production to direct it against the parasite by designing chemical entities able to trap these radicals to give secondary transient radical species toxic for th e parasite. Using this approach, a hit has been identified.
Wissenschaftliches Gebiet
Programm/Programme
Aufforderung zur Vorschlagseinreichung
FP6-2004-LIFESCIHEALTH-5
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