A systematic analysis of protein kinases in malaria parasites to identify, validate and prioritise novel drug targets

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Malaria is a major infectious disease of man, with 500 million clinical cases thought to result in more than one million deaths each year. In the absence of a licensed vaccine, the emergence of resistance to available drugs continues to be a serious problem. There is a sustained need for new, affordable drugs that contrasts starkly with the level of investment pharmaceutical companies allocate to the problem. In view of limiting resources, the validation and prioritisation of potential drug targets is particularly important. The large family of protein kinases encoded in the parasite‘s genome is of particular interest for drug target identification, because members of the kinase family have in the past been shown to play key essential function in the parasite‘s life cycle progression. The aim of the research programme proposed here is to identify, validate and prioritise the most promising target kinases encoded in the parasite‘s genome and to study their biological functions in parasite development and transmission. In the proposal we define the essential and desirable properties of parasite protein kinases that qualify as high priority targets and suggest six experimental filters, which we will use to evaluate candidate kinases. On the one hand our analysis will initially look at members of a family of calcium-dependent protein kinases, for which we have already assembled a strong body of evidence suggesting their suitability as targets. On the other hand, we propose a multidisciplinary and collaborative approach that will combine the genetic tractability of Plasmodium berghei, a malaria parasites infecting rodents, and bioinformatics, biochemical and structural studies on protein kinases of P. falciparum, to carry out an unbiased, genome-wide analysis of Plasmodium protein kinases with the aim of identifying novel, high priority targets for pharmacological intervention.