Malaria is caused by large-scale infection of the body’s red blood cells with Plasmodium parasites. After invading a red blood cell the parasite over the course of two days, grows and then replicates forming 20 or so offspring that burst out and invade many more red blood cells. These cycles of growth, replication, egress and invasion require different parasite molecular motors to work in the right order and only when required. To coordinate the different parasite machines, messages have to be sent around the cell to turn systems on and off as required. The messages are in the form of small signalling molecules like calcium ions, lipids and cyclic nucleotides.
These signalling molecules act by switching certain proteins such as kinases on and off which then in turn switches on or off other proteins by phosphorylating them. With our collaborators we have been developing compounds that mimic certain chemical messengers thereby interfering with the natural signalling processes in the parasite and essentially paralysing it. We have been particularly interested in blocking the ability of parasites to invade new red blood cells as this part of the cell cycle involves many machines and signalling processes only found the parasite and not the human host. Invading parasites could be particularly vulnerable to drug targeting since any delay in invading new red blood cells would leave them open to attack from the human immune system.
We have established that a parasite surface protein called AMA1, which helps to strongly anchor the parasite to the red blood cell prior to invasion, is activated by a kinase inside the parasite. We have with our collaborators developed drugs that potently block the kinase mediated phosphorylation of AMA1 thereby blocking invasion. We have also developed a second set of drugs the prevent some kinases including the AMA1 kinase, from being switched off after they have done their jobs and this is very toxic to the parasites as well.