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Targeting malaria transmission through interference with signalling in Plasmodium falciparum gametocytogenesis

Final Report Summary - SIGMAL (Targeting malaria transmission through interference with signalling in Plasmodium falciparum gametocytogenesis)

Inhibiting transmission of the malaria parasite from infected humans to the mosquito vector would be of considerable interest in the context of malaria control, especially in order to prevent the dissemination of drug-resistant genotypes. Since only sexual forms of the parasite (the gametocytes) are infective to the mosquito, blocking gametocytogenesis would prevent transmission. The molecular control of gametocytogenesis is not understood. The laboratories of the 'Targeting malaria transmission through interference with signalling in Plasmodium falciparum gametocytogenesis' (SIGMAL) project have independently brought significant contributions to the characterisation of components of signalling pathways, some of which are likely to be involved in differentiation, and proteins expressed at the onset of gametocytogenesis, such as Pfg27 and Pfs16.

Specific objectives of the network are:

- to establish a map of protein-protein interactions for molecules expressed at the onset of gametocytogenesis, identified within the network by conventional and genome-wide approaches;
- to define the role of phosphorylation of Pfg27, an RNA-binding phosphoprotein essential to sexual development whose structure is solved, integrating biochemical, functional and structural approaches;
- to establish the role that protein kinases and proteins expressed specifically in early gametocytes play in differentiation, using a reverse genetics approach;
- to elucidate the organisation of signalling pathways thought to be involved in gametocytogenesis, such as the cyclic nucleotide and MAPK pathways, central components of which have been characterised in our laboratories;
- to establish biochemical assays for signalling protein kinases, and optimise such assays to medium throughput screening.

Some of the kinases have now been validated by reverse genetics as targets for transmission-blocking intervention. One of these, Pfnek-4 has been adapted to MTS and over 12,700 compounds have been tested on this target.

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