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Targetting malarial cell cycle kinases


Plasmodium falciparum cell cycle regulators are promising targets for novel anti-malarial drug design. This application is firmly based in the post-genomic era where the identification of novel drug targets is greatly facilitated by the availability of the P. falciparum genomic databases. P. falciparum cell cycle regulators are promising drug targets because of their predicted essential roles in regulating the pathogen's life-cycle. We have determined the structure of PfPK5. the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. A comparison of CDK structures from these two evolutionarily remote organisms suggests that the fold and the mechanism of inactivation of monomeric CDKs are highly conserved. The first aim of this project is to employ X-ray crystallographic studies to guide the development of potent and selective small molecule ATP-competitive inhibitors of P. falciparum protein kinase 5 (PfPK5), a member of the P. falciparum cyclin-dependent protein kinase family. Homologues of this enzyme in other eukaryotes play an essential role in regulating cell cycle progression. These compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for anti-malarial drug development. The second aim of the project is to employ biochemical and biophysical methods to characterise CDK/cyclin complexes. This will explore the evolutionary conservation of the structural mechanisms that regulate the eukaryotic cell cycle. The final aim is to characterise P. falciparum cyclin 4 (Pfcyc-4) a novel member of the cyclin family that shows a distinct pattern of expression in the erythrocytic stages of the parasite's life cycle.

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