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Targeting the Malarial Protein Kinase PfCDPK1

Keith Ansell1, Hayley Jones1, David Whalley1, Simon Osborne1, Nathalie Bouloc1,Tim Chapman1, Jon Large1, Claire Wallace1, Kristian Birchall1, Andy Merritt,1Justin Bryans,1 Catherine Kettleborough1, Debbie Taylor1, Robert Moon2 , Barbara Clough2, Judith Green.2and Tony Holder.2

1. Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, London NW7 1AD.

2. Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA

Malaria remains one of the most important infectious diseases of the developing world. Up to 3 billion people are at risk, and each year there are 300-660 million clinical cases and at least 1 million children in Africa alone die of malaria. Resistance to existing anti-malarial drugs is widespread and there is an urgent need to develop new chemotherapeutic agents. Calcium-dependent protein kinases (CDPKs) are found only in plants and alveolates and are unique in that they are bipartite enzymes, containing a kinase domain and a regulatory domain. They are directly regulated by Ca2+, via its interaction with the calmodulin-like regulatory domain of the kinase. P. falciparum CDPK1 is encoded by an essential gene and is responsible for phosphorylation of components of the molecular motor that drives parasite invasion of red blood cells. We have identified potent and selective inhibitors of PfCDPK1 kinase activity through medicinal chemistry efforts based on 3 hit series originally identified from a high throughput screen of our in-house compound collection. These compounds inhibit growth of P. falciparum in vitro with low nanomolar potencies and are also potent inhibitors of P. vivax CDPK1. Infection with P. vivax represents the major cause of malaria outside of Africa and new drugs are needed in particular to prevent relapse. We have also cloned and expressed PfCDPK4 and PfCDPK5 in order to profile the inhibitors against these related P. falciparum kinases and report on their mechanism of action through expression of ATP site gatekeeper mutants.

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