Artemisinin-based drug combinations are highly effective treatments of malaria, but resistance is spreading in southeast Asia and treatment failures are getting more common in Africa. The steep reductions in annual malaria cases and mortality observed over more than a decade have stalled in recent years raising fears that the situation will worsen in the coming years. There are some promising new antimalarial drug candidates undergoing clinical testing, however attrition rates are high and it is not certain that any of these drugs will make it all the way to patients. It is therefore essential that alternative drugs are developed to tackle the problem of drug resistant malaria. This project is focused on developing a drug that targets cyclic nucleotide phosphodiesterase enzymes (PDEs). Researchers have identified highly potent inhibitors of malaria parasite PDEs in vitro and have obtained Wellcome Trust funding to work with chemists to optimise these inhibitors with the objective to generate proof of concept for PDEs as antimalarial drug targets in vivo. Bloomsbury SET funding allows them to express the parasite PDEs and to generate co-crystal structures with selected inhibitors to inform the medicinal chemistry compound design effort. Achievement of these objectives will significantly enhance success of obtaining follow-on funding to support the next steps of this project which will involve fine tuning of potency against the parasite PDEs and reduction of activity against human PDE enzymes to ensure we have a strong safety profile as part of pre-clinical testing and testing in humans.
Dr David Baker, Professor of Malaria Parasite Biology (LSHTM)
Dr Mark Gardner, Computational and Medical Chemist (Salvensis)
Dr Alan Brown, Medical Chemist (Salvensis)
Dr James Duffy, Medical Chemist (Medicine for Malaria Venture)