READ-UP - Redox antimalarial drug discovery

Background:

The READ-UP project aims at identifying antimalarial drug candidates (one candidate and two back-ups). The project will begin with a hit identified in the first series, enlarging it, and designing other series through the different steps of drug discovery and hit-to-lead optimisation from the pilot scale production towards pre-clinical studies.

Artemisinin, the natural antimalarial product, and its derivatives are increasingly important in the treatment of drug-resistant malaria as they are the most potent 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. The READ-UP project starts from the unique mode of action of artemisinins to develop a completely new approach: initiate radical transient species within the parasitised red blood cell in such a way that no endoperoxide bridge is required.

Problem:

Malaria remains one of the most devastating diseases of the developing world, causing more than 1 million deaths and 300-500 million clinical cases each year. Although four Plasmodium species infect humans (P. falciparum (P. f.), P. vivax, P. ovale and P. malariae), most deaths are caused by the severe complications of P. f. malaria. Malaria-related morbidity and mortality are increasing, mainly as a consequence of drug resistance as observed with the two most widely used antimalarial drugs: chloroquine and sulfadoxine-pyrimethamine. To combat malaria, new drugs are urgently needed.

In this context, the READ-UP project brings together public organisations and SMEs to drive a research project aimed at identifying a new drug candidate for malaria. Starting from one series with antimalarial activity, which was created by a public laboratory of the consortium using a new approach, the project, coordinated by a pharmaceutical SME, will realise hit-to-lead optimisation through molecular modelling, testing of new chemical entities in vitro and in vivo and pharmacological, pharmacokinetics, toxicological and mechanisms studies.

Aim:

Following the drug discovery process until the pilot-scale production, the objective is to propose one antimalarial drug candidate with two back-ups for further pre-clinical studies.

An initial series of new stable compounds has been developed by UPS. In a first synthetic series, several compounds presented anti-plasmodial properties and preliminary in vitro and in vivo studies led to the identification of one hit. Based on the excellent in vitro and in vivo results already obtained, the READ-UP project will develop new structural analogues using the same innovative approach. The in vitro and in vivo results obtained will be further improved by the application of optimisation techniques, through the 'Drug Discovery' process that the READ-UP partners will implement. The project aims at enlarging this first series and designing other series to identify new antimalarial drug candidates (one drug candidate and two back-ups) through the different steps of drug discovery and hit optimisation. Moreover, the READ-UP innovative strategy should allow designing chemically stable compounds, which may have a longer duration of action in vivo.

Coordinator:

Partners: