MALKIN · Targetting malarial cell cycle kinases
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-03-01 → 2006-02-28
- EU contribution
- €158,479
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - MALKIN (Targetting malarial cell cycle kinases)
Plasmodium falciparum, the protozoan parasite responsible for the lethal form of human malaria, causes between 1 and 3 million deaths every year, mostly among children in sub-Saharan Africa. Within eukaryotes, protein kinases are involved in key processes of the life cycle of a cell. Such proteins have been identified in P. falciparum and thus are promising targets for novel anti-malarial drug design. Firmly based in the post-genomic era, this work consisted of structure determination by X-ray crystallography of complexes between two P. falciparum protein kinases and small molecule ATP-competitive inhibitors: (i) PfPK5 which shows 56% sequence homology to human Cyclin Dependent Kinase 1 (CDK1), and (ii) PfPK7 which is an atypical kinase and cannot be ascribed to any protein kinase family. Fourteen inhibitors were tested on an active PfPK5/cyclin A complex. Nu6102 and Purvalanol B which show respectively IC50 values of 215 nM and 130 nM are the two most interesting compounds, but are more potent on human CDKs. This information will be of use in the design of more selectivePfPK5 inhibitors. The structure of PfPK7, determined in this project, is the first of an atypical kinase. It shows novel characteristics which it may be possible to exploit for the design of selective and specific inhibitors. Using new technologies we have identified a putative substrate for PfPK7, PfRab11B. This substrate is the first plasmodial kinase substrate to be identified. We have also identified 5 compounds that bind tightly to PfPK7 in vitro and that have IC50 values in the range xxx-yyy. Co-crystallisation trials and biochemical assays to characterise these compound as PfPK7 inhibitors are in progress.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OXFORDCoordinatorCity levelUnited Kingdom
Links
Data: CORDIS, © European Union